British Journal of Obstetrics and Gynaecology May 1998, Vol. 105, pp. 536-540

Fetal growth velocity in the prediction of intrauterine growth retardation in a low risk population

*Philip Owen Consultant, tKhalid S. Khan Specialist Registrar *Department of Obstetrics, Glasgow Royal Maternity Hospital, Glasgow; TDepartment of Obstetrics and Gynaecologv, Ninewells

Hospital and Medical School, Dundee

Objective To determine whether fetal growth velocity derived from two antenatal ultrasound measurements in the third trimester, 28 days apart, can identify infants born with anthropometric features of intrauterine growth retardation.

Design Prospective observational study. Setting Department of obstetric ultrasound, Ninewells Hospital, Dundee.

Subjects Two hundred and seventy four low risk women participating in a longitudinal study of serial fortnightly ultrasound in pregnancy.

Methods Growth velocities of the fetal abdominal area and bi-parietal diameter were calculated from the third from last and last measurements prior to delivery. Receiver Operator Characteristics curves were employed to determine an optimal cutoff point for velocity to predict intrauterine malnourishment.

Main outcome measures Likelihood ratios for fetal abdominal area and bi-parietal diameter growth velocity in the prediction of growth retarded infants with skinfold thickness < 10th centile; ponderal index < 25th centile, or mid-arm circumference to occipito-frontal circumference ratio (MAC:OFC ratio) of less than -1 SD. A likelihood ratio of > 10 generates significant changes in the pre-test probability of growth retardation, whereas a likelihood ratio of 5 to 10 generates only moderate changes.

Results Fetal abdominal area velocity predicted growth retardation with likelihood ratio 10.4 (95% CI 3.9 to 26) for skinfold thickness; likelihood ratio 9.5 (95% CI 4.6 to 19) for ponderal index; a likelihood ratio 4.7 (2-3 to 8-4) for MAC:OFC. Bi-parietal diameter velocity predicted growth retardation with likelihood ratio 6-5 (95% CI 1 -9 to 20) for skinfold thickness but did not predict low ponderal index or MAC:OFC ratio.

Conclusions Fetal abdominal area velocity is useful in identifying infants with reduced skinfold thickness or low ponderal index. Prospective evaluation of serial ultrasound and velocity calculation in a selected population at increased risk of growth failure and a clearer understanding of the relative significance of the different neonatal anthropometric measures of impaired growth achievement is necessary before the estimation of growth velocity can be recommended in clinical practice.

INTRODUCTION The distinction between the constitutionally small and the growth retarded infant is being increasingly accepted as the limited relevance of birthweight alone as an indi- cator of intrauterine growth achievement and perinatal outcome is re~ognised’-~. Abnormalities of neonatal body constitution believed to reflect impaired fetal nutri- tion appear to be more useful indicators of adverse peri- natal and long term outcomes than birthweight a l ~ n e ~ - ~ . The identification of apparently appropriate birthweight

Correspondence: Mr P. Owen, Department of Obstetrics, Glasgow Royal Maternity Hospital, Rottenrow, Glasgow, G4 ONA.

infants with anthropometic features of intrauterine mal- nourishment underlines the heterogeneous nature of growth retardation’.

Reliable antenatal identification of the growth retarded infant at risk of adverse outcome might improve allocation of monitoring resources, with the possibility of improving perinatal outcome. Construction of growth velocity standards allows fetal growth velocity, as deter- mined from two ultrasound measurements, to be quanti- fied. Subsequently the ability of growth velocity to identify the growth retarded infant can be evaluated. This is the first study to assess the ability of growth velocity to identify infants with features of intrauterine growth retardation in a low risk population.

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F E T A L G R O W T H V E L O C I T Y A N D P R E D I C T I O N O F I U G R 537

METHODS Three hundred and thirteen women attending the ante- natal clinic at Ninewells Hospital, Dundee were enrolled into the study. Entry criteria were singleton pregnancy, gestational age of < 85 days confirmed by crown-rump length measurement, and the absence of recognised risk factors for accelerated or retarded fetal growth, including a history of a previous infant who was small for gestational age, existing medical disor- ders or heavy smoking (> 20 cigarettes per day). All the participants were scanned for fetal anomaly at 18 weeks gestation and thereafter were sequentially entered into one of the four (identified as A, B, C, D), pre-deter- mined scanning schedules (n = number continuing in the study):

A. 22,26,30,32,34,36,38,40 weeks, (n = 72)

B. 23,27,31,33,35,37,39,41 weeks, (n = 72)

C. 24,28,32,34,36,38,40 weeks, (n = 63)

D. 25,29,33,35,37,39,41 weeks, (n = 67)

All ultrasound measurements were made using an Aloka SSD-650 real-time ultrasound scanner using a 3.5 MHz probe by the same observer (PO). Crown- rump length was measured in a standard manner, using a frozen on-screen image and electronic caliperss. Gestational age was calculated with reference to crown- rump length and not menstrual data9. The bi-parietal diameter was estimated from leading edge to leading edge at the level of the cavum septum pellucidurnlo. The fetal abdominal area was measured at the level of the umbilical vein" by tracing the outline of the trunk on- screen. The fetal abdominal area measurement is chosen in preference to the abdominal circumference since a measurement of area is more relevant theoretically to a two dimensional image than a linear measurement. While circumference measurements or measures of the abdominal diameter are appropriate when the outline is circular, only the area is truly representative of a cross- sectional fetal profile if the outline is elliptical or irregu- lar12. Three measurements were made of each variable and the mean for each recorded. Measurements were recorded without knowledge of values recorded at ear- lier gestational ages. Intra-observer reproducibility was assessed by calculating the coefficients of variation by measuring 10 volunteers outwith the study in the third trimester. Values of 1.45% and 0.4% were obtained for the fetal abdominal area and bi-parietal diameter, respectively.

Fetal growth velocity was determined for both bi- parietal diameter and fetal abdominal area (where possi- ble) from the third last and last scan before delivery (ie,

28 day separation). The velocity standard deviation score (Z score) is calculated from the following formula:

Velocity Z score = daily increment-reference mean increment

standard deviation

The reference mean increment and standard devia- tion refer to the gestational age-specific values deter- mined from previously published reference ranges for ultrasound growth velo~ity '~.

Neonatal data Birthweight was adjusted to take account of the mothers' height and mid-pregnancy weight and accorded a centile position according to gestational age, sex and birth-~rder'~. Skinfold thickness was measured (P.O.) on the second or third day of life using Holtain calipers15. Three measurements were made at the sub- scapular and triceps areas on the child and the mean measurement recorded and a centile position obtained after adjustment for gestational age and sex16. The occipito-frontal circumference (OFC) was measured with a tape measure and the mean of three measure- ments recorded. The mid-arm circumference (MAC) was measured at a point halfway between the acromion and the olecranon process of the ulna of the right arm which was flexed at ninety degrees. The mean of three measurements was recorded and the mid-arm circum- ference to occipito-frontal circumference (MAC:OFC) ratio calculated. The values were compared with refer- ence data for term, Caucasian infants". The baby's length was measured on a standard neonatal anthro- pometer on the third day of life. The mean of three mea- surements was recorded, the ponderal index calculated and centile position obtained1*. Neonatal measurements were made without knowledge of the intrauterine growth velocity results.

Statistical analysis

The ability of growth velocity to identify infants with anthropometric features of intrauterine malnourishment was evaluated by constructing receiver-operator charac- teristic (ROC) curves and quantifying the areas under the curve^*^^^^. An optimal cutoff point was identified using the best combination of true positive and false positive rates from the curve. This cutoff was used to calculate the sensitivity, specificity, positive and nega- tive predictive values for bi-parietal diameter and fetal abdominal area velocities. In addition, the likelihood ratio, a more clinically relevant measure of diagnostic accuracy, was computed. The likelihood ratio indicated by how much a given test result will raise or lower the pre-test probability of delivering a growth-retarded

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538 P. O W E N & K. S . K H A N

infant. For a positive test result, a likelihood ratio of > 10 generated significant changes in the pre-test proba- bility of growth retardation whereas likelihood ratio of 5 to 10 generated only moderate changes. For a negative result, a likelihood ratio of < 0.1 generated significant changes, while a likelihood ratio of 0.1-0.2 generated only moderate changes in the pre-test probabilitya'. We examined the implications of likelihood ratio generated with growth velocity calculation for the different pre- test probabilities by using Bayes' theorem to generate post test probabilities as shown below:

Pre-test probability =prevalence of intrauterine growth retardation.

Pre-test odds = pre-test probability / (1- pre-test probability)

Post test odds = likelihood ratio x pre-test odds.

Post-test probability = post-test odds / (1+ post-test odds)

RESULTS Two hundred and seventy-four volunteers continued in the study. The compliance, demographic data and obstetric features of the study population were pre- sented in an earlier study13. Two hundred and sixty infants (95%) were delivered at > 37 weeks of gestation. Twenty-two (8%) and 11 (4%) had adjusted birth- weights < 10th and 3rd centiles, respectively. Skinfold thickness, ponderal index and MAC:OFC ratios were available in 238,257 and 237 cases, respectively. Some cases were missed due to early discharge or could not be categorised because the reference data used for neonatal anthropometry does not extend to premature births. In addition, a small number of cases were unsuitable for analysis because the ultrasound data was inadequate for the calculation of velocity because of difficulty in obtaining measurements due to fetal position. Twenty- six infants (10.9%) had one or both skinfold thicknesses < 10th centile, 40 (15.6%) had a ponderal index < 25th centile, and 17 (7%) had MAC:OFC ratio below -lSD.

The areas under the ROC curves are presented in Table 1. Values can range from 0 to 1 , with values > 0.5 consistent with a discriminative capacity. Bi-parietal diameter velocity had no discriminatory ability for the identification of a ponderal index < 25th centile or MAC:OFC ratio < -1 SD and is not considered further in the prediction of these outcomes. Optimal cutoff velocity Z scores were derived from the ROC curves; the relevant test performance based on likelihood ratios are presented in Table 2. A positive test result in fetal abdominal area velocity had a likelihood ratio of 10.4 (95% CI 3-9 to 26) for skinfold thickness < 10th centile; a likelihood ratio of 9.5 (95% CI 4.6 to 19) for ponderal

index < 25th centile, and a likelihood ratio of 4-7 (2.3 to 8.4) for MAC:OFC ratio of less than -1 SD. Bi-parietal diameter velocity had a likelihood ratio of 6-5 (95% Cl 1.9 to 20) for a skinfold thickness <: 10th centile. Large changes in pre-test probability of growth retardation occurred only with a positive test result for fetal abdom- inal area velocity using skinfold thickness and ponderal index as outcome measures. Negative test results pro- duced only minimal changes in pre-test probabilities.

DISCUSSION This is the first study to evaluate the ability of appropri- ately derived measures of fetal growth velocity to pre- dict the delivery of infants with anthropometric features of intrauterine malnourishment from a population tradi- tionally considered to be low risk. Single estimates of fetal size perform poorly in the prediction of infants with low skinfold thickness, although estimated fetal weight performs best, which is not surprising since there is inevitably a relation between skinfold thickness and b i r t h ~ e i g h t ~ , ~ ~ . Other studies have evaluated mea- sures of fetal body proportionality in an effort to iden- tify the growth retarded infant, but the fetal ponderal index23 and the femur length to abdominal circumfer- ence (FL:AC) ratio perform p ~ o r l y ~ ~ ~ ~ ~ , with the abdon- minal Circumference performing better than the FL:AC ratio26.

Previous studies of serial ultrasound have demon- strated a relation between poor growth velocity and intrapartum operative delivery and admission to the neonatal unit in both low risk and small for gestational age population^^^-^^. In a population of 104 antenatally detected SGA pregnancies, Chang et have demon- strated that impaired growth, expressed as a change in estimated fetal weight 2 score, is predictive of a low ponderal index and reduced skinfold thickness.

In our study the likelihood ratios for the prediction of growth retardation were typically higher for fetal abdominal area velocity than bi-parietal diameter veloc- ity. This is to be expected if we consider that the brain- sparing phenomenon occurs in human fetuses subjected to intrauterine malnutrition, as it appears to operate under experimental conditions in primates and lamb^^'.^^. It can be argued that the bi-parietal diameter is not the most appropriate estimate of head growth since it is one-dimensional, and that head circumference or area would be more appropriate. Data for head circumfer- ence and area are not available for this population, but in a study of serial ultrasound in SGA pregnancies, change in head circumference was a poorer predictor of apparently growth retarded infants than either change in abdominal circumference or estimated fetal weighPo.

The actual values for the anthropometric parameters chosen as measures of outcome in this study are arbi-

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F E T A L G R O W T H V E L O C I T Y A N D P R E D I C T I O N O F I U G R 539

Table 1. Summary Receiver-operator characteristics (ROC) curves and test properties of growth velocity in the prediction of intrauterine growth retardation. BPD = bi-parietal diameter; FAA = fetal abdominal area. MAC/OFC = mid-arm circumference to occipito-frontal circumference ratio; NIA = not applicable; Z = standard deviation.

Velocity parameter

FAA FAA FAA BPD BPD BPD

Outcome measure

Skinfold thickness* Ponderal index** MAC/OFCt Skinfold thickness* Ponderal index** MAC/OFCt

Positive Area under Cutoff Z Sensitivity Specificity prediction ROC curve score % % %

Negative prediction

%

0.14 -2 30 97 57 0.75 -1.55 40 96 64 0.69 -1 '5 47 90 27 0.7 1 -2 17 97 44 0.54 NIA NIA N/A N/A 0.53 NIA NIA N/A N/A

91 90 96 91

NIA N/A

*<loth centile; **<25th centile; t<-lSD.

Table 2. Pre-test probability (prevalence), likelihood ratios and post-test probability of intrauterine growth retardation using various growth velocity measurements. + = positive test result, - = negative test result; BPD = Bi-parietal diameter. FAA = Fetal abdominal area. MACiOFC = Mid-arm circumference to occipito-frontal circumference ratio.

Pre-test Likelihood ratio Post-test Change in Velocity Outcome probability (95% CI) probability probability parameter measure % - % % + FAA Skinfold thickness 1 1 10.4 (3.9-26) 0.72 (0'5-0'8) 51 46

< 10th centile 9 2 FAA Ponderal index 16 9.5 (4.6-19) 0.62 (0.4-0.7) 64 48

< 25th centile 10 6 FAA MAC/OFC 7 4.7 (2.3-8.4) 0.5 (0.3-0.8) 27 20

<-I sd 4 3 BPD Skinfold thickness I I 6.5 (1.9-20) 0.8 (0.6-0'9) 44 33

< 10th centile 9 2

trary since there are no published studies comparing val- ues of skinfold thickness, ponderal index and MAC:OFC for the identification of the malnourished infant at greatest risk of morbidity. The deficiency of appropriately defined outcomes for the conduct of ante- natal studies aimed at identifying pregnancies at risk of perinatal morbidity has previously been highlighted33. In the absence of established outcomes we have presented results for three different anthropometric measurements.

We have used likelihood ratios to evaluate growth velocity, because expressing the performance of a test in these terms readily enables us to assess how useful the test might be in clinical practice; this depends on the change in pre-test probability that occurs from the test result. In our opinion this is the best method of evaluat- ing diagnostic tests. Traditionally, concepts of sensitiv- ity and specificity are used to assess diagnostic tests, but this is less useful*l. Evidence for the usefulness of a test is considered to be very strong when the likelihood ratio exceeds lo2'. In this study a fetal abdominal area veloc- ity 2 score of -2 or less has a llkelihood ratio of 10.37 (95% CI 3.95 to 26.34) in the prediction of an infant with either one or both triceps and subscapular skinfold thickness below the tenth centile. Using cutoff values of

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-1.55 and -1.5 for fetal abdominal area velocity, respectively, likelihood ratios are slightly lower for the prediction of a ponderal index below the 25th centile and are considerably lower for a MAC:OFC ratio less than -1 SD. The changes in post test probabilities pre- sented in Table 2 clearly demonstrate the superiority of fetal abdominal area velociy compared with bi-parietal diameter velocity.

The likelihood ratios suggest that a positive test result for fetal abdominal area velocity is of value in identifying infants with reduced skinfold thickness or a low ponderal index. Likelihood ratios can be converted into a measure of probability taking into account the pre-test probability which is dependent upon the preva- lence of the disorder in a particular population". This concept is supported by the fact that at low prevalence in a low risk population even likelihood ratio of > 10 do not result in very substantial changes in probability. In a high risk group however, the pre-test probabilities or prevalence are higher, and so the likelihood ratios reported in Table 2 would be expected to produce sub- stantial changes in probability.

Before recommending the use of growth velocity in clinical practice we would encourage further study

540 P. O W E N & K . s. K H A N

involving the prospective evaluation of serial ultra- sound and velocity calculation in a selected population at increased risk of growth failure, together with a clearer understanding of the relative prognostic signifi- cance of the different neonatal anthropometric measures of growth achievement.

Acknowledgement Mr P. Owen gratefully acknowledges the financial sup- port for this study provided by Wellbeing.

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Received I1 June I997 Returnedfor revision 4 September 1997 Accepted 6 January 1998

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