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Journal of Prenatal Medicine logoLink to Journal of Prenatal Medicine
. 2009 Oct-Dec;3(4):62–65.

Reference interval for fetal biometry in Italian population

Maurizio Giorlandino 1, Francesco Padula 1, Pietro Cignini 1, Marialuisa Mastrandrea 1, Roberto Vigna 1, Giorgia Buscicchio 2, Claudio Giorlandino 1
PMCID: PMC3279111  PMID: 22439050

Abstract

Objectives:

To validate new references charts and equations for fetal biometry in an Italian unselected population.

Methods:

A cross-sectional study involving 4896 women with singleton viable pregnancies, at Artemisia Fetal Maternal Medical Centre between May 2009 and December 2009. Each woman was scanned only once, between 14+0 and 40+0 weeks of gestation. The fetal standard biometric measurements were recorded. For each parameter, regression models were fitted to estimate the percentile at each gestational age. In order to be compared to other reference equations, the fetal biometric measurements at each gestational age were expressed as Z-scores.

Results:

New fetal charts and references equations for Italian population were developed according to the recommend multistep statistical procedure.

Conclusion:

To our knowledge this is the first Italian study with the largest sample size ever reported in the literature. In addiction, our newer charts of reference centiles for fetal biometric measurements are useful in the obstetrical clinical practice for the Italian population.

Introduction

An appropriate evaluation of fetal biometry represents the cornerstone in the fetal growth assessment giving that an abnormal growth may be associated with an adverse perinatal outcome and may require a specific obstetrical care (1).

Many variables affect fetal growth (2, 3, 4) including physiological and pathological changes, such as maternal height and weight, drug or tobacco exposure, fetal sex, ethnicity (5), genetic syndromes, congenital anomalies and placental failure. Therefore, each particular population or ethnic group should have their own reference charts for the different fetal anthropometrical variables in order to provide the most accurate fetal assessment. Furthermore, fetal nomograms need to be revised regularly as fetus is growing up in the last decades (6, 7) and need to be constructed in accordance with the recommended method of analysis (8, 9). In fact, the choice of a standard approach is crucial, because inaccurate centiles obtained from an inferior method may mislead the obstetrician as to the true state of health of development of the fetus and increase the chance of suboptimal clinical care. The World Health Organization recommends the expression of measurements as Z-scores in order to allow relevant statistical analysis (10, 11).

The aim of our study is to develop new reference charts and equations for fetal standard biometry between 14 and 40 weeks of gestation in a cohort of healthy Italian women with low-risk singleton viable pregnancies.

Methods

The study included a population of 4896 Italian women undergoing ultrasound examination between the 14th and 40th weeks of gestation at Artemisia Fetal Maternal Medical Centre, between May 2009 and December 2009. Inclusion criteria were singleton pregnancies in Italian women with low-risk pregnancy. Exclusion criteria were multiple pregnancy, abnormal karyotype, congenital malformations, gestational or maternal diseases (such as hypertension and diabetes mellitus), no firsttrimester dating based on crown-rump length (CRL). Cases with low birth weight, preterm delivery or other prenatal complications were not excluded. Gestational age was based on the last menstrual period and in all cases adjusted according to the CRL measured in the first trimester ultrasound. Every fetus was measured only once for the study. All measurements were performed by 5 different obstetric sonographers (MG, PC, FP, MLM, RV) using the following equipments: GE Voluson 730, GE E8 and GE Voluson 730 Pro (General Electric Healthcare, USA).

Measurements of the biparietal diameter (BPD) and head circumference (HC) were obtained from a transverse axial plane of the fetal head showing a central midline echo broken in the anterior third by the cavum septum pellucidi and demonstrating the anterior and posterior horns of the lateral ventricle. The BPD was measured from the outer margin of the proximal skull to the inner margin of the distal skull. The HC was measured fitting a computer-generated ellipse to include the outer edges of the calvarial margins of the fetal skull.

The abdominal circumference (AC) was measured fitting a computer-generated ellipse through a transverse section of the fetal abdomen at the level of the stomach and bifurcation of the main portal vein into its right and left branches. The femur length (FL) was measured in a longitudinal scan where the whole femural diaphysis was seen almost parallel to the transducer and measured from the greater trochanter to the lateral condyle. In the third trimester, particular care was taken not to include the ephiphysis.

Statistical analysis was performed using SPSS 16.0 and STATISTICA 7.0. The data were analyzed as recommended by Altman and Royston (8, 9).

The normality of measurements at each week of gestation was assessed using the Kolmogorov–Smirnov test. Given the large sample size, statistically significant nonnormality was accepted unless the normal plot showed clear deviation from a straight line. In order to obtain normal ranges for fetal measurements, a multistep procedure based on regression model has been used, according to the recommended methodology.

A centile curve is calculated using the following formula: Centile = M + K x SD

where K is the corresponding centile of the standard Gaussian distribution, M is the mean and SD is the standard deviation of the mean of the fetal measurements for each gestational age.

The mean is estimated by the fitted values from an appropriate polynomial regression curve of the measurement of interest on gestational age. A cubic polynomial model was used (y = a + b × GA + c × GA2 + d × GA3) unless the R2 statistic and/or the fitted curve was not satisfactory.

The standard deviation is obtained through the following steps: the residuals were calculated as the absolute value of the differences between the fitted curve and the original data for each patient and then multiplied by a corrective constant equal to (=1.253). These were finally regressed on gestational ages by using a simple linear equation (y = a + b x GA). The fitted values give the age-specific SD estimates.

The standard deviation is obtained through the following steps: the residuals were calculated as the absolute value of the differences between the fitted curve and the original data for each patient and then multiplied by a corrective constant equal to (=1.253). These were finally regressed on gestational ages by using a simple linear equation (y = a + b x GA). The fitted values give the age-specific SD estimates.

Finally, these predictive mean and SD equations allow calculating any required centile, replacing the value in the centile formula. The constant K may be ±0.674 for the determination of the 25 th and 75 th centiles, ±1.282 for the 10th and 90th centiles, ±1.645 for the 5th and 95th centiles, ±1.96 for the 2.5 th and 97.5 th centiles, ±2.33 for 1st and 99 th centiles, ±2.58 for 0.5th and 99.5 th centiles.

In order to compare our new reference equations with previously published ones, we calculated Z-scores of the median, 5th and 95th percentiles, according the following formula:

Z-score = (XGA-MGA)/SDGA

where XGA is the measured value at a known gestational age (GA), MGA is the mean value obtained with the reference equation used at this GA, and SDGA is the SD associated with the mean value at this GA obtained with the reference equation. Results were presented graphically across GA.

Results

Full biometric measurements (BPD, HC, AC, FL) were obtained for 4896 fetuses. The best-fitted regression model describing the relationship between biometric parameters and GA was the cubic model. Data analysis showed that neither the use of fractional polynomials nor the logarithmic transformation improved the fitting of the curves. The corresponding regression equations for the mean are as follows:

BPDmean=12.707 - (0.771 x GA) + (0.186 x GA2) - (0.00291 x GA3) (R2=96.6)

HCmean=18.841 + (0.506 x GA) + (0.576 x GA2) - (0.00973 x GA3) (R2=97.4)

ACmean= -40.349 + (7.209 x GA) + (0.214 x GA2) - (0.00383 x GA3) (R2=95.2)

FLmean=-32.045 + (3.597 x GA) - (0.00917 x GA2) - (0.000353 x GA3) (R2=97.2)

SDs across GA were fitted using a simple linear model. Fits for SDs were as follows:

BPDSD= 1.174 + 0.069 x GA

HCSD= 1.795 + 0.295 x GA

ACSD= -1.447 + 0.542 x GA

FLSD= 0.676 + 0.061 x GA

Tables 1-4 show the centile charts with 0.5th, 1 th, 2.5 th, 5 th, 10 th, 50 th, 90 th, 95 th, 97.5 th, 99 th, 99. th centiles fitted for all biometric parameters. Figure 1 illustrates the goodness of fit of our model by showing the raw data for the main measurements in obstetrical practice with the fitted 5 th, 50 th and 95 th centiles. We graphically compared our Zscores to the ones derived by the 5 th, 50 th and 95 th percentiles calculated for the main biometric parameters of two previously published sets of reference equations (12, 13) (Figure 2).

Table 1 - .

Fitted centiles of biparietal diameter (BPD) (mm)

GA 0,5° 2,5° 10° 25° 50° 75° 90° 95° 97,5° 99° 99,5°
14 24,9 25,4 26,2 26,9 27,6 28,9 30,4 31,8 33,1 33,9 34,6 35,4 35,9
15 27,5 28,0 28,8 29,5 30,3 31,7 33,2 34,7 36,0 36,8 37,5 38,3 38,9
16 30,2 30,8 31,6 32,3 33,1 34,5 36,1 37,6 39,0 39,8 40,5 41,4 41,9
17 33,0 33,6 34,5 35,2 36,0 37,5 39,1 40,6 42,1 42,9 43,7 44,5 45,1
18 35,9 36,5 37,4 38,1 39,0 40,5 42,1 43,8 45,2 46,1 46,9 47,8 48,4
19 38,8 39,5 40,4 41,2 42,1 43,6 45,2 46,9 48,4 49,3 50,1 51,0 51,7
20 41,8 42,5 43,4 44,2 45,1 46,7 48,4 50,1 51,7 52,6 53,4 54,4 55,0
21 44,8 45,5 46,5 47,3 48,2 49,8 51,6 53,4 55,0 55,9 56,7 57,7 58,4
22 47,8 48,5 49,5 50,4 51,3 53,0 54,8 56,6 58,2 59,2 60,1 61,1 61,7
23 50,8 51,5 52,6 53,4 54,4 56,1 58,0 59,8 61,5 62,5 63,4 64,4 65,1
24 53,8 54,5 55,6 56,5 57,5 59,2 61,1 63,0 64,7 65,8 66,7 67,7 68,4
25 56,7 57,5 58,5 59,4 60,5 62,3 64,2 66,2 67,9 69,0 69,9 71,0 71,7
26 59,6 60,3 61,4 62,4 63,4 65,3 67,3 69,3 71,1 72,1 73,1 74,2 74,9
27 62,4 63,1 64,3 65,2 66,3 68,2 70,2 72,3 74,1 75,2 76,2 77,3 78,0
28 65,0 65,8 67,0 68,0 69,1 71,0 73,1 75,2 77,0 78,2 79,2 80,3 81,1
29 67,6 68,4 69,6 70,6 71,7 73,7 75,8 77,9 79,9 81,0 82,0 83,2 84,0
30 70,0 70,8 72,0 73,1 74,2 76,2 78,4 80,6 82,6 83,7 84,8 86,0 86,8
31 72,3 73,1 74,4 75,4 76,6 78,6 80,9 83,1 85,1 86,3 87,4 88,6 89,4
32 74,4 75,3 76,5 77,6 78,8 80,9 83,1 85,4 87,5 88,7 89,8 91,0 91,9
33 76,3 77,2 78,5 79,6 80,8 82,9 85,2 87,6 89,7 90,9 92,0 93,3 94,1
34 78,1 78,9 80,2 81,3 82,6 84,8 87,1 89,5 91,6 92,9 94,0 95,3 96,2
35 79,5 80,4 81,8 82,9 84,2 86,4 88,8 91,2 93,4 94,7 95,8 97,2 98,1
36 80,8 81,7 83,1 84,2 85,5 87,8 90,2 92,7 94,9 96,3 97,4 98,8 99,7
37 81,8 82,7 84,1 85,3 86,6 88,9 91,4 93,9 96,2 97,5 98,7 100,1 101,0
38 82,5 83,5 84,9 86,1 87,4 89,8 92,3 94,9 97,2 98,6 99,8 101,2 102,1
39 83,0 83,9 85,4 86,6 88,0 90,3 92,9 95,5 97,9 99,3 100,5 101,9 102,9
40 83,1 84,1 85,5 86,8 88,2 90,6 93,2 95,9 98,3 99,7 100,9 102,4 103,4
41 82,9 83,9 85,4 86,6 88,1 90,5 93,2 95,9 98,3 99,8 101,0 102,5 103,5

Table 4 - .

Fitted centiles of femur length (FL) (mm)

GA 0,5° 2,5° 10° 25° 50° 75° 90° 95° 97,5° 99° 99,5°
14 11,6 12,0 12,5 13,0 13,6 14,5 15,5 16,6 17,5 18,1 18,5 19,1 19,5
15 14,6 14,9 15,5 16,0 16,6 17,6 18,7 19,7 20,7 21,3 21,8 22,4 22,8
16 17,5 17,9 18,5 19,0 19,6 20,6 21,7 22,8 23,8 24,4 25,0 25,6 26,0
17 20,3 20,7 21,4 21,9 22,5 23,6 24,7 25,9 26,9 27,5 28,1 28,7 29,1
18 23,1 23,5 24,2 24,8 25,4 26,5 27,7 28,9 29,9 30,6 31,1 31,8 32,2
19 25,8 26,3 27,0 27,5 28,2 29,3 30,6 31,8 32,9 33,6 34,2 34,8 35,3
20 28,5 29,0 29,7 30,3 31,0 32,1 33,4 34,7 35,8 36,5 37,1 37,8 38,3
21 31,1 31,6 32,3 33,0 33,7 34,9 36,2 37,5 38,7 39,4 40,0 40,7 41,2
22 33,7 34,2 34,9 35,6 36,3 37,5 38,9 40,3 41,5 42,2 42,8 43,6 44,1
23 36,2 36,7 37,5 38,1 38,9 40,1 41,5 42,9 44,2 45,0 45,6 46,4 46,9
24 38,6 39,1 39,9 40,6 41,4 42,7 44,1 45,6 46,9 47,6 48,3 49,1 49,6
25 41,0 41,5 42,3 43,0 43,8 45,1 46,6 48,1 49,5 50,3 50,9 51,8 52,3
26 43,2 43,8 44,6 45,4 46,2 47,5 49,1 50,6 52,0 52,8 53,5 54,3 54,9
27 45,4 46,0 46,9 47,6 48,5 49,9 51,4 53,0 54,4 55,3 56,0 56,9 57,4
28 47,6 48,2 49,1 49,8 50,7 52,1 53,7 55,3 56,8 57,7 58,4 59,3 59,9
29 49,6 50,2 51,2 51,9 52,8 54,3 55,9 57,6 59,1 60,0 60,7 61,6 62,3
30 51,6 52,2 53,2 54,0 54,9 56,4 58,1 59,8 61,3 62,2 63,0 63,9 64,5
31 53,5 54,2 55,1 55,9 56,8 58,4 60,1 61,9 63,4 64,4 65,2 66,1 66,8
32 55,3 56,0 57,0 57,8 58,7 60,3 62,1 63,9 65,5 66,4 67,3 68,2 68,9
33 57,0 57,7 58,7 59,6 60,5 62,2 64,0 65,8 67,4 68,4 69,3 70,2 70,9
34 58,7 59,4 60,4 61,3 62,3 63,9 65,8 67,6 69,3 70,3 71,2 72,2 72,9
35 60,2 60,9 62,0 62,9 63,9 65,6 67,5 69,4 71,1 72,1 73,0 74,0 74,7
36 61,7 62,4 63,5 64,4 65,4 67,2 69,1 71,0 72,8 73,8 74,7 75,8 76,5
37 63,0 63,8 64,9 65,8 66,8 68,6 70,6 72,6 74,4 75,4 76,4 77,4 78,2
38 64,3 65,1 66,2 67,1 68,2 70,0 72,0 74,0 75,9 77,0 77,9 79,0 79,8
39 65,5 66,2 67,4 68,3 69,4 71,3 73,4 75,4 77,3 78,4 79,3 80,5 81,2
40 66,5 67,3 68,5 69,4 70,6 72,5 74,6 76,7 78,6 79,7 80,7 81,8 82,6
41 67,5 68,3 69,5 70,5 71,6 73,5 75,7 77,8 79,8 80,9 81,9 83,1 83,9

Figure 1.

Figure 1

Fitted 5th , 50th and 95th centile curves superimposed on the raw data for biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL). Dashed lines represent the 5th and 95th centiles and the thick central one the 50th centile.

Figure 2.

Figure 2

Comparison of our new equations with Salomon (solid lines) and Snijders (dashed lines) references for biparietal diameter (a), head circumference (b), abdominal circumference (c) and femur length (d). Dotted gridlines represent the expected Z-scores for 5th, 50th and 95th centiles, i.e. -1.645, 0 and 1.645 respectively.

Discussion

The need for reference curves for a specific population arises from the observation that fetal growth depends on many factors, including ethnicity. In fact in literature a variety of chart references are described, varying from different populations. On the other hand, there has been an increasing value of fetal biometric parameters, thus the needing of updated chart references that reflect the trend of fetal growth. The first statistical models developed for Italian fetuses date back to 1987, including biparietal diameter, head circumference and abdomen circumference from 1,426 healthy fetuses (14). More complete

Italian fetal size charts will be published almost 20 years later, including head, abdomen and long bones measurements, although the number of fetuses was only 626 and the Authors did not specify the formula for calculating the standard deviation, letting the comparison with their curves be impossible (15).

The construction of reference interval for fetal variables is crucial as inaccurate centiles produced by inferior methods may mislead an abnormal growth that may be associated with an adverse perinatal outcome and require a specific obstetrical care. We followed the method described by Altman and Chitty and Royston and subsequently confirmed by Royston, in which they claim the need of an approach based on statistical techniques and the term “normal range” should be substituted by “reference interval” since the former implies that any observation outside the range indicates an “abnormality”, which is not necessarily the case.

Table 2 - .

Fitted centiles of head circumference (HC) (mm)

GA 0,5° 2,5° 10° 25° 50° 75° 90° 95° 97,5° 99° 99,5°
14 97 98 101 102 105 108 112 116 120 122 124 126 127
15 107 109 111 113 115 119 123 127 131 133 135 138 139
16 118 119 122 124 126 130 135 139 143 145 147 150 151
17 129 130 133 135 137 142 146 151 155 157 159 162 164
18 139 141 144 146 149 153 158 163 167 170 172 174 176
19 151 152 155 157 160 165 170 175 179 182 184 187 189
20 162 164 166 169 172 176 182 187 191 194 197 199 201
21 173 175 178 180 183 188 193 199 204 207 209 212 214
22 184 186 189 192 195 200 205 211 216 219 221 224 227
23 195 197 200 203 206 211 217 223 228 231 234 237 239
24 205 208 211 214 217 222 228 234 240 243 246 249 251
25 216 218 221 224 228 233 239 246 251 255 257 261 263
26 226 228 232 235 238 244 250 257 262 266 269 272 275
27 236 238 242 245 248 254 261 267 273 277 280 284 286
28 245 248 251 254 258 264 271 278 284 288 291 294 297
29 254 257 260 264 267 274 281 288 294 298 301 305 307
30 262 265 269 272 276 283 290 297 303 307 311 315 317
31 270 273 277 280 284 291 298 306 312 316 320 324 326
32 277 280 284 288 292 298 306 314 320 325 328 332 335
33 283 286 291 294 298 305 313 321 328 332 336 340 343
34 289 292 296 300 304 312 319 327 335 339 343 347 350
35 294 297 301 305 309 317 325 333 341 345 349 353 356
36 298 301 305 309 314 321 330 338 346 350 354 359 362
37 300 304 308 312 317 325 333 342 350 354 358 363 366
38 302 306 310 315 319 327 336 345 353 357 361 366 369
39 303 307 311 316 320 329 337 346 355 359 364 368 372
40 303 306 311 316 321 329 338 347 355 360 365 370 373
41 301 305 310 314 319 328 337 347 355 360 364 370 373

Table 3 - .

Fitted centiles of abdominal circumference (AC) (mm)

GA 0,5° 2,5° 10° 25° 50° 75° 90° 95° 97,5° 99° 99,5°
14 76 78 80 82 84 88 92 96 100 102 104 106 108
15 86 87 90 92 94 99 103 108 112 114 116 119 120
16 95 97 100 102 105 109 114 119 123 126 128 131 133
17 105 107 110 112 115 120 125 130 135 138 140 143 145
18 115 117 120 123 126 131 136 142 147 150 153 156 158
19 125 127 130 133 136 142 148 154 159 162 165 168 170
20 135 137 140 143 147 152 159 165 171 174 177 181 183
21 144 147 150 154 157 163 170 177 183 186 189 193 196
22 154 157 161 164 168 174 181 188 194 198 202 205 208
23 164 166 170 174 178 185 192 199 206 210 214 218 220
24 173 176 180 184 188 195 203 211 218 222 226 230 233
25 183 186 190 194 198 206 214 222 229 234 238 242 245
26 192 195 200 204 208 216 224 233 241 245 249 254 257
27 201 204 209 213 218 226 235 244 252 257 261 266 269
28 210 213 218 223 228 236 245 254 263 268 272 277 281
29 218 222 227 232 237 246 255 265 274 279 283 289 292
30 227 231 236 241 246 255 265 275 284 289 294 300 303
31 235 239 245 249 255 264 275 285 294 300 305 310 314
32 243 247 253 258 264 273 284 295 304 310 315 321 325
33 251 255 261 266 272 282 293 304 314 320 325 331 335
34 258 262 268 274 280 290 302 313 323 330 335 341 345
35 265 269 276 281 287 298 310 322 332 339 344 351 355
36 271 276 282 288 295 306 318 330 341 348 353 360 364
37 277 282 289 295 301 313 325 338 349 356 362 369 373
38 283 288 295 301 308 320 332 345 357 364 370 377 382
39 288 293 301 307 314 326 339 352 364 371 378 385 390
40 293 298 306 312 319 332 345 359 371 379 385 392 397
41 297 303 310 317 324 337 351 365 378 385 392 399 405

The representation of the fetal equations into Z-scores, as suggested by Salomon, lead to evaluate the effect of the reference curve chosen on the quality of screening for growth abnormalities. Indeed, knowing only the mean and the standard deviation, the Z-score allows a comparison between different curves. In our series, the graphical representation highlights that Italian fetuses have smaller HC and AC than English and French fetuses. This may suggest that Italian fetuses are smaller than other populations or that it may arise from the different methods used by Salomon in the measurement of HC and AC, which were manually calculated from BPD and FOD and the two maximum abdominal diameters, respectively. Finally Italian fetuses seem to have much smaller femurs than the English, at least until the beginning of the third trimester, but similar length than French femurs.

Conclusion

Our new Italian reference interval charts for fetal biometry and reference equations have clinical relevance since they provide sonographers new reference equations in the obstetrical practice.

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