Ultrasound Assessment of Abnormal Fetal Growth David A. Nyberg, Alfred Abuhamad, and Yves Ville A ccurate pregnancy dating is the most important initial step in modern obstetric management. Precise knowledge of gestational age is essential for the management of pregnancies and in particular fetal growth abnormalities. Unfortunately, dating by menstrual history is often unreliable. Up to 40% of women are not certain of their dates and even when they are, their wide distribution tends to over-estimate gestational age (GA) when compared with ultrasound.1 Dating based on ultrasound is often more predictive than even certain menstrual dates, when ultrasound in performed in the first half of the pregnancy.2-5 Overestimation of gestational age is common when based on menstrual dates. This has the effect of underestimating the rate of preterm delivery6 and overestimating the number of postdate pregnancies. In a routinely scan-dated population, Gardosi et al7 found that 72% of inductions performed for post-term pregnancy (⬎ 294 days) according to menstrual dates were not actually post-term according to ultrasound dating. Early ultrasound dating can therefore substantially reduce the number of pregnancies considered postdates, and decrease the need for term inductions. Ultrasound Dating First Trimester In general, the earlier the ultrasound, the more accurate the assessment of dates. This is logical because all fetuses begin at the same size yet may vary dramatically in size by term. Because of the high degree of accuracy, dating by ultrasound in the first half of pregnancy has become a routine part of antenatal care in many institutions around the world. Before 6 weeks, dating can be done by measurement and observation of the gestational sac.8 The gestational sac is visible as early as 4 weeks, and should always be visible by 5 weeks (Fig 1). The size of the gestational sac can be correlated with gestational age.9 Because the mean sac diameter (MSD) grows at a rate of 1 mm per day, gestational age can be estimated by the formula: Gestational age (days) ⫽ 30 ⫹ MSD (mm).10 Among all measurements, maximum embryo’s length at 6 to 10 weeks (Fig 2) and crown rump length (CRL) measurement up to 14 weeks are the most accurate at determining GA (Table 1). The random error is in the range of 4 to 8 days SD (standard deviation) at the 95th percentile.11-16 The largest study that uses a strict methodology is that of Wisser et al.16 They highlight potential pitfalls of previous studies and show a predictivity interval of 4.7 days SD on 160 in vitro fertilization (IVF) patients, including 21 multiple pregnancies. Second and Third Trimesters When the CRL is above 60 mm, other biometric parameters are more useful for dating the pregnancy.17 Standardized measurements include the biparietal diameter, head circumference, femur length, humerus length, and abdominal circumference. These grow in a predictable way and so can be correlated with GA (Table 2). Virtually any other bone or organ can be measured and compared with GA. The head circumference is the most predictive parameter of gestational age between 14 and 22 weeks’ gestation as it predicts GA by 3.4 days.5 Other parameters, such as the biparietal diameter (BPD), abdominal circumference (AC), and femur length (FL) also have good accuracy during the second trimester. Combining various biometric parameters improves the prediction of GA slightly over the head circumference (HC) alone.18 In the third trimester, the best single measurement of Address reprint requests to David A. Nyberg, MD, 10401 E. McDowell Mtn Ranch Rd, #2-372, Scottsdale, AZ 85255. © 2004 Elsevier Inc. All rights reserved. 0146-0005/04/2801-0002$30.00/0 doi:10.1053/j.semperi.2003.10.010 Seminars in Perinatology, Vol 28, No 1 (February), 2004: pp 3-22 3 4 Abnormal Fetal Growth Figure 1. Gestational sac at 5 weeks of gestation. A yolk sac is faintly visualized. GA based on standard biometry is the femur length. The BPD and HC reflect head size, which in turn reflects brain growth. Although head measurements primarily reflect the calcified calvarium, they are subject to variation based on compression of the calvarium. BPD and HC can be reliably measured from 13 weeks of gestation when ossification of the parietal bones of the skull has occurred. It should be noted that head measurements are slightly larger in male fetuses compared to female fetuses,19 and this difference can produce systematic errors in dating in the range of 1.5 to 2.5 days.20,21 The occipito-frontal diameter (OFD) is measured in the same plane as the BPD with the calipers placed on the outer skull table (Fig 3). The HC can be either directly measured or can be calculated from the BPD and OFD [HC ⫽ (BPD ⫹ OFD) ⫻ 1.57]. The direct method is less than 2% bigger than the calculated measurement. Fetal head shape variations (dolichocephaly, brachycephaly) and fetal position can affect head measurements, particularly the BPD in which case the HC is preferable. Femur length is the most commonly obtained long bone measurement and is reproducibly measured from 13 weeks onwards (Fig 4). Humerus length is also frequently obtained, especially during the second trimester. The femur grows 3 mm per week from 14 to 27 weeks and 1 mm per week in the third trimester. Reported accuracy for pregnancy dating ranges from 1 week in the second trimester to 3 to 4 weeks at term.22Femur length after 18 to 19 weeks correlates with maternal height,23 and also correlates with neonatal length. Long bone measurements also vary with ethnicity with longer measurements in Black populations.24-26 The AC is a measure of fetal girth. It includes soft tissues of the abdominal wall as well as a measure of internal organs, primarily the liver. Unlike other commonly used fetal measurements, it is not influenced by bone. The importance of AC is reflected by the fact that, at term, 95% of newborns are found to be within 20% of expected length of 20 cm, whereas the weight may vary by 100% or more. Therefore, differences in weight must be explained primarily by variations in girth. Not surprisingly, then, the AC is among the least predictive measures of fetal age but the most predictive of fetal growth.27-29 The AC is measured on an axial plane at the level of the stomach and the bifurcation of the main portal vein into the right and left branches taking care of having a section as round as possible, not deformed by the pressure of the probe (Fig 5). The most accurate should approximate a perpendicular plane to the spine at the level of the hepatic vein. Ribs should show a symmetric covering of the lateral contours. The AC shows linear growth with a mean of 11 to 12 mm per week throughout gestation. Mean AC and percentiles for abdominal circumference are shown in Table 3. Assessment of Fetal Size Estimation of Fetal Weight The best overall measure of fetal size is obtained by estimating fetal weight. Numerous formulae for estimating fetal weight have been described and used (Table 4).30-34 With standard biometry, some formulas use head measurements and AC, others use long bone measurements and AC, and others use all 4 measurements. The AC is included in all commonly used formulas of estimated fetal weight, and AC also strongly influences fetal weight estimates.35 Weight estimates based on AC alone have also been reported.36,37 Virtually any fetal bone or organ can be mea- Nyberg, Abuhamad, and Ville 5 Figure 2. Growth during the first trimester. (A) Embryonic length at 7 weeks of gestation. The crown rump length is indicated. The yolk sac and amnion are also visualized although discrete embryonic landmarks are not seen. (B) Scan at 12 weeks shows remarkable growth of the fetus. Crown rump length measurement is indicated by red arrow. Fetal detail is now appreciated. sured and be shown to grow in a predictable pattern. In an attempt to improve the accuracy of estimating fetal weight, it is tempting to add many more measurements to standard biometry. However, it is probably more worthwhile to ensure an accurate measurement of the AC rather than adding other measurements of biometry. Complicated formulas of fetal weight have not been found to be more predictive than those relying on standard biometry. Fetal weight estimates that are based on an artificial neural network model have also been proposed.38 Regard- less of the method, estimation of fetal weight is limited by the imprecision of fetal measurements, especially during the third trimester. In experienced hands, nearly 80% of estimated weights are within 10% of the actual birth weight and most of the remaining are within 20% of birth weight. However, sonographic accuracy decreases with less experienced sonographers.39 Also a number of studies have documented that prediction of fetal weight by ultrasound may be limited. For example, one study by Baum et al39 found that sonographic estimation of fetal 6 Abnormal Fetal Growth Table 1. Predicted Menstrual Age From Crown Rump Length (CRL) Measurements Crown Rump Length (mm) Menstrual Age (weeks) 0.2 0.3 0.4 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.8 2.9 3.0 3.1 3.2 3.4 3.5 3.7 3.8 4.0 4.1 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.5 5.6 5.7 5.8 5.9 6.0 6.1 6.2 6.3 6.4 6.5 6.6 5.7 5.9 6.0 6.1 6.3 6.4 6.6 6.7 6.9 7.0 7.1 7.3 7.4 7.6 7.7 7.9 8.0 8.1 8.3 8.4 8.6 8.7 8.9 9.0 9.1 9.3 9.4 9.6 9.7 9.9 10.0 10.1 10.3 10.4 10.6 10.7 10.9 11.0 11.1 11.3 11.4 11.6 11.7 11.9 12.0 12.1 12.2 12.3 12.3 12.4 12.5 12.6 12.6 12.7 12.8 12.8 12.9 Table 1. (Cont’d) Crown Rump Length (mm) Menstrual Age (weeks) 6.7 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 13.0 13.1 13.1 13.2 13.3 13.4 13.4 13.5 13.6 13.7 13.8 13.8 13.9 14.0 14.1 14.2 14.2 14.3 Data from Hadlock FP, Shah YP, Kanon DJ, et al: Fetal crown-rump length: Reevaluation of relation to menstrual age (5-18 weeks) with high-resolution real-time US. Radiology 182:501-505, 1992. weight was no better than clinical or patient estimates at term. Weight formulas that include BPD, HC, AC, and FL results in a mean absolute error of around 10%.40,41 Some formulas for estimating fetal weight are volume based and they would be expected to be more accurate in predicting fetal weight.31,32 However, these volume-based equations have not been shown to be more accurate in other studies and result in large systematic errors.42 Some formulae have been specifically designed for premature babies43,44 However, specific formulas for premature or very low birth weight fetuses have not been found to be more accurate in estimation of fetal weights than standard formulas by others.45 Three dimensional ultrasound has been used to estimate fetal weight46,47 and theoretically this method should result in improved estimation of fetal weight compared to estimations based on standard biometry (Fig 6). However, one limitation is that the most commonly used three-dimensional ultrasound systems have a limited field of view that does not include the entire fetus. As an alternative, 3-D ultrasound can evaluate specific fetal structures rather than the entire fetus. For example, Song et al48 measured thigh volume with three-dimensional ultrasound and reported that this method was more accu- Nyberg, Abuhamad, and Ville 7 Table 2. Predicted Fetal Measurements at Specific Gestational Age in Centimeters GA (Weeks) BPD HC FL AC 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 1.7 2.1 2.5 2.9 3.2 3.6 3.9 4.3 4.6 5.0 5.3 5.6 5.9 6.2 6.5 6.8 7.1 7.3 7.6 7.8 8.0 8.3 8.5 8.7 8.8 9.0 9.2 9.3 9.4 6.8 8.2 9.7 11.1 12.4 13.8 15.1 16.4 17.7 18.9 20.1 21.3 22.4 23.5 24.6 25.6 26.6 27.5 28.4 29.3 30.1 30.8 31.5 32.2 32.8 33.3 33.8 34.2 34.6 0.7 1.1 1.4 1.7 2.1 2.4 2.7 3.0 3.3 3.6 3.8 4.1 4.4 4.6 4.9 5.1 5.4 5.6 5.8 6.1 6.3 6.5 6.7 6.9 7.1 7.2 7.4 7.6 7.7 4.6 6.0 7.3 8.6 9.9 11.2 12.5 13.7 15.0 16.2 17.4 18.5 19.7 20.8 21.9 23.0 24.0 25.1 26.1 27.1 28.1 29.1 30.0 30.9 31.8 32.7 33.6 34.4 35.3 Abbreviations: BPD, biparietal diameter; HC, head circumference; FL, femur length; AC, abdominal circumference. BPD ⫽ ⫺3.08 ⫹ 0.41*GA ⫺ 0.000061*GA2 (SD 3 mm) HC ⫽ ⫺11.48 ⫹ 1.56*GA ⫺ 0.0002548* GA2 (SD 1 cm) AC ⫽ ⫺13.3 ⫹ 1.61*GA ⫺ 0.00998*G GA2 (SD 1.34 cm) FL ⫽ ⫺3.91 ⫹ 0.427*GA ⫺ 0.0034* GA2 (SD 3 mm) Data from Hadlock FP, Deter RL, Harrist RB, et al: Estimating fetal age: Computer assisted analysis of multiple fetal growth parameters. Radiology 152:497-501, 1984. Figure 3. Transverse view of the fetal head obtained at the level of the thalami at 22 weeks of gestation. Note the BPD diameter and OFD. day. Fetal length continues in a predictable way, growing approximately one half centimeter per week throughout pregnancy. By the end of the first half of pregnancy, the fetus is about half its eventual length, but only about one seventh of its ultimate weight. The fetus adds much of its weight during the third trimester. When growth is expressed as a change proportional to current weight, a constant deceleration is observed after 14 weeks.50 Estimated Fetal Weight Percentiles An appropriate method of assessing fetal growth is to determine the estimated weight percentile. rate than two-dimensional ultrasound for predicting fetal weight during the third trimester of pregnancy. Similarly, Schild et al47 combined three-dimensional volume estimates of the thigh, upper arm, and abdomen and found it to be superior to two-dimensional biometry for estimating fetal weights. Also, Lee et al49 describe a model for estimation of fetal weight based on fractional thigh volume and AC. Assessment of Fetal Growth The gestational period is characterized by extraordinary fetal growth. During the first trimester, the embryo grows approximately 1 mm per Figure 4. Longitudinal view of the femur obtained at 18 weeks of gestation. Note that femural measurement is obtained as the distance from the outer edges of each metaphysic. 8 Abnormal Fetal Growth Figure 5. Transverse view of the fetal abdomen obtained at 28 weeks of gestation at the level of the abdominal circumference. Note the stomach (S), spone (sp), and intraabdominal portion of the umbilical vein (UV). GA.54 More accurate neonatal charts have been derived from neonates with accurate ultrasound dating (Fig 7).55,56 A number of individual variables affect fetal growth including maternal height, maternal and paternal weight, parity, ethnicity, maternal smoking, as well as the gender of the fetus.57,58 Paternal height also plays a minor role.59 Among other variables, smaller fetal size tends to reflect both maternal and paternal birth weights. Magnus et al58 found the mean maternal birth weight was significantly less among those who had experienced 2 small for GA (SGA) births compared to those with no SGA births (3,127 ⫾ 54 g v 3,424 ⫾ 22 g). Interestingly, the mean paternal birth weight was also lower (3,497 ⫾ 88 g v 3,665 ⫾ 24 g) from affected pregnancies with 2 previous SGA births. Table 3. Reference Values for Abdominal Circumference (cm) Abdominal Circumference (cm) This requires comparison of estimated fetal weight with expected weight for age. A commonly used weight percentile chart is presented in Table 5 and Figure 7. Once the fetal weight has been estimated and compared with expected weight for age, it is a simple matter to determine the estimated weight percentile. Normal values are generally accepted as between the 10th and 90th percentiles, although these cutoffs are arbitrary and the 5th and 95th percentiles are more predictive. Expected weight standards have been generated either by weighing babies at birth, or by using sonographic estimates of fetal weight.17 Variable results have been published.51 Some of these differences may reflect the wide heterogeneity in ethnic composition, physical characteristics and socioeconomic status of the populations studied. Limitations of such standards should be recognized and have been reviewed by Altmann and Chitty.52 Weight charts based on clinical dates showed a false flattening of birth weight curves at term secondary to overestimation of GA based on the menstrual history.53 In contrast, ultrasoundderived growth charts do not show a flattening near term (Fig 7). One problem with birth weight charts based on birth weights is that premature births or stillbirths tend to be small for Percentiles Menstrual Age (weeks) 3rd 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0 27.0 28.0 29.0 30.0 31.0 32.0 33.0 34.0 35.0 36.0 37.0 38.0 39.0 40.0 6.4 7.5 8.6 9.7 10.9 11.9 13.1 14.1 15.1 16.1 17.1 18.1 19.1 20.0 20.9 21.8 22.7 23.6 24.5 25.3 26.1 26.9 27.7 28.5 29.2 29.9 30.7 10th 50th 90th 97th 6.7 7.9 9.1 10.3 11.5 12.6 13.8 14.9 16.0 17.0 18.1 19.1 20.1 21.1 22.0 23.0 23.9 24.9 25.8 26.7 27.5 28.3 29.2 30.0 30.8 31.6 32.4 7.3 8.6 9.9 11.2 12.5 13.7 15.0 16.2 17.4 18.5 19.7 20.8 21.9 23.0 24.0 25.1 26.1 27.1 28.1 29.1 30.0 30.9 31.8 32.7 33.6 34.4 35.3 7.9 9.3 10.7 12.1 13.5 14.8 16.3 17.6 18.8 20.0 21.3 22.5 23.7 24.9 26.0 27.2 28.3 29.4 30.4 31.5 32.5 33.5 34.4 35.4 36.4 37.3 38.2 8.3 9.7 11.2 12.7 14.1 15.5 17.0 18.3 19.7 20.9 22.3 23.5 24.8 26.0 27.1 28.4 29.5 30.6 31.8 32.9 33.9 34.9 35.9 37.0 38.0 38.9 39.9 From Callen et al. Data from Hadlock FP, Deter RL, Harrist RB, Park SK. Estimating fetal age: Computer-assisted analysis of multiple fetal growth parameters. Radiology 152:497-501, 1984. Nyberg, Abuhamad, and Ville 9 Table 4. Various Formulas used to Estimate Fetal Weight (in grams unless specified) Warsof 1977 BPD, AC Shepard 1982 BPD, AC Roberts 1985 BPD, HC, AC, FL Combs HC, AC, FL Hadlock 1984 FL, AC Hadlock 1984 BPD, HC, FL, AC Hadlock 1985 BPD, HC, FL, AC Hadlock 1985 FL, AC Log10 (Wt in kg) ⫽ ⫺1.599 ⫹ (0.144 ⫻ BPD) ⫹ (0 ⫻ AC) ⫺ (0.000111 ⫻ AC ⫻ BPD2) Log10 (Wt in kg) ⫽ ⫺1.7492 ⫹ (0.166 ⫻ BPD) ⫹ (0.046 ⫻ AC) ⫺ (0.002646 ⫻ AC ⫻ BPD) Log10 (Wt) ⫽ 1.6758 ⫹ (0.01707 ⫻ AC) ⫹ (0.042478 ⫻ BPD) ⫹ (0.05216 ⫻ FL) ⫹ (0.01604 ⫻ HC) Wt ⫽ 0.23718 ⫻ AC2 ⫻ FL ⫹ (0.03312 ⫻ HC3) Log10 (Wt) ⫽ 1.3598 ⫹ (0.051 * AC) ⫹ (0.1844 * F (.0037 *AC *FL)) Log10 (Wt) ⫽ 1.5115 ⫹ (0.0436 * AC) ⫹ (0.1517 FL) ⫺ (0.00321 * FL * AC) ⫹ (0.0006923 * BP HC) Log (Wt) ⫽ 1.3596 ⫺ 0.00386*FL*AC ⫹ 0.0064 *HC ⫹ 0.00061*BPD*AC ⫹ 0.0424 *AC ⫹ 0.174 *FL Log10 (Wt) ⫽ 1.304 ⫹ .05281*AC ⫹ 0.1938*FL ⫺ 0.004 *AC*FL Abbreviations: Wt, weight; BPD, biparietal diameter; HC, head circumference; FL, femur length; AC, abdominal circumference. Shepard MJ, Richards VA, Berkowitz RL, et al. An evaluation of two equations for predicting fetal weight by ultrasound Am J Obstet Gynecol 1982;142:47. Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body and femur measurements: a prospective study. Am J Obstet Gynecol 1985;152:333-7. Hadlock FP, Harrist RB, Carpenter RJ, et al. Sonographic estimation of fetal weight. Radiology 1984;150:535-40. Roberts AB, Lee AJ, James AG. Ultrasonic estimation of fetal weight: a new predictive model incorporating femur length for the low-birth-weight fetus. J Clin Ultrasound 1986;13:555-559. Warsof SL, Gohari P, Berkowitz RL, et al. The estimation of fetal weight by computer-assisted analysis. Am J Obstet Gynecol 1977;128:881. Compared with population-based birth weight charts, some authors have found that individual birth weight standards better correlate with fetal outcome.60 For example, Clausson et al61 found that individual growth standards better detected fetuses at risk of stillbirth, neonatal death, and low Apgar scores. Sciscione et al62 also conclude that adjusting birth weight standards for maternal and infant characteristics may improve prediction of adverse outcomes. An example of individualized growth standards may be found on the internet.63 Multiple gestations have similar growth curves to singletons until the third trimester. Ong et al64 found that the growth pattern of the AC for twins is nearly identical to singletons until 32 weeks and then begins to gradually fall from singleton curves, whereas the femur length was more similar to singletons. Serial Ultrasound In clinical practice when abnormal growth is suspected, serial ultrasound examinations are more helpful than a single point on the growth curve. Different methods of quantifying and ex- Figure 6. Three-dimensional ultrasound. This could give an accurate volume estimate to determine fetal weight. However, it is difficult to capture the entire fetus in a limited field of view available for most three-dimensional ultrasound systems. 10 Abnormal Fetal Growth Table 5. Fetal Weight Percentiles, in grams, by Gestational Age (GA) GA (Weeks) 3rd 10th 50th 90th 97th 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 26 34 43 54 69 87 109 135 166 204 247 298 357 424 500 586 681 787 903 1029 1163 1306 1457 1613 1773 1936 2098 2259 2414 2563 2700 2825 2935 29 37 48 61 77 97 121 150 185 227 275 331 397 472 556 652 758 876 1005 1145 1294 1454 1621 1795 1973 2154 2335 2514 2687 2852 3004 3144 3266 35 45 58 73 93 117 146 181 223 273 331 399 478 568 670 785 913 1055 1210 1379 1559 1751 1953 2162 2377 2595 2813 3028 3236 3435 3619 3787 3934 41 53 68 85 109 137 171 212 261 319 387 467 559 664 784 918 1068 1234 1415 1613 1824 2048 2285 2529 2781 3036 3291 3542 3785 4018 4234 4430 4602 44 56 73 92 117 147 183 227 280 342 415 500 599 712 840 984 1145 1323 1517 1729 1955 2196 2449 2711 2981 3254 3528 3797 4058 4307 4538 4749 4933 NOTE. Ln (wt) ⫽ 0.578 ⫹ 0.332 MA ⫺ 0.00354 * MA2) SD ⫽ 12.7% of predicted weight. Data from ref 55. evaluated include cheek-to-cheek diameter, soft tissue thickness of the thigh or arm, and measurement of subcutaneous fat. Fetal abdominal subcutaneous fat measurement correlates with other measurements of fetal nutrition. For example, Donoghue et al67 found that fetuses with an abdominal subcutaneous fat measurement of 5 mm or less were more likely to have an AFI (amniotic fluid index) ⬍ 8 cm, an AC ⬍ 10th percentile, and show lower postnatal parameters of growth including a lower mean ponderal index and a decreased skinfold thickness at birth. Matsumoto et al68 developed a “fetal nutrition score” by qualitative assessment of the amount of subcutaneous tissue present at 3 locations (face, ribs, and buttocks) on prenatal three-dimensional ultrasound. The fetal nutrition score strongly correlated with birth weight and neonatal nutritional score, and also correlated with Apgar score, but not with umbilical cord arterial blood pH. Abnormal Growth Deviations of normal fetal growth can be seen by at least 20 weeks of gestation69 and probably as early as the first trimester in some cases (see Smith, this issue). Abnormal growth may represent subnormal growth (growth restriction), or abnormally accelerated growth. Of the two, growth restriction is more strongly related to fetal abnormalities and adverse outcome. pressing serial changes in fetal size have been described, including the use of conditional percentiles.65,66 Standards based on serial measurements would seem a more appropriate technique for quantifying fetal growth as they account for fetal size earlier in gestation, which is an important determinant of subsequent fetal growth and correct for the mathematical phenomenon of “regression towards the mean.”66 Use of first trimester ultrasound as a baseline has also permitted more accurate growth curves.55,56 Other Measures of Fetal Growth Other measures of fetal growth may not attempt to estimate fetal weight or size, but rather look at more specific areas. Soft tissues that have been Figure 7. Fetal weight percentiles. Expected weight (middle line) and weight percentiles. (Data from ref 55). Nyberg, Abuhamad, and Ville Identification of fetuses with growth disturbances depends to a large extent on sonographic assessment. Growth disturbances may also be suspected based on clinical findings of decreased fundal height measurement and poor maternal weight gain, in addition to identification of maternal risk factors, such as diabetes or hypertension. Various metabolic analytes in the maternal serum have been associated with normal and abnormal fetal growth. Of these, the association between fetal leptin concentrations and fetal weight appear the strongest.70 However, to date, evaluation of maternal analytes has not been incorporated into clinical practice. Intrauterine Growth Restriction Identification of affected fetuses with intrauterine growth restriction (IUGR) is important because of a higher risk of fetal mobidity and mortality compared to appropriately grown fetuses matched for gestational age.71 Long-term follow-up studies have shown an increased incidence of physical handicap and neurodevelopmental delay in growth restricted fetuses.72,73 The presence of chronic metabolic acidemia in utero, rather than actual birth weight appears to be the best predictor of long-term neurodevelopmental delay.74 In pregnancies with growth restricted fetuses, timing of the delivery is the most critical step in clinical management. Balancing the risk of prematurity with the risk of long-term neurodevelopmental delay is a serious challenge facing physicians involved in the care of these pregnancies. The term “small for gestational age” (SGA) is commonly used to describe all fetuses who are small and, by this definition, represent a heterogeneous group of both normal and “growthrestricted” fetuses. We reserve the term “IUGR” to fetuses who are SGA and who show other evidence of chronic hypoxia or malnutrition. Nevertheless, the terms SGA and IUGR are frequently used interchangeably. The most common definition of SGA is a fetus whose weight is below the 10th percentile for gestational age. However, this definition is not universally accepted. Some authors may define it has fetal weight below the 5th or 3rd percentile, AC below the 10th, 5th, or 3rd percentile, or lack of normal growth of the abdominal circumference on serial examinations. Other may 11 categorize growth disturbance based on absolute weight at birth such as ⬍2,500 or ⬍1,500 g. However, this obscures the distinction between smallness caused by prematurity and that caused by growth restriction. Risk Factors Causes and associations for IUGR are shown in Table 6 The most common associations are with maternal hypertension, and/or a history of IUGR in previous pregnancies. Conversely, a his- Table 6. Causes and Associations With IUGR Maternal Pregnancy induced hypertension/pre-eclampsia Severe chronic hypertension Severe maternal diabetes mellitus Collagen vascular disease Heart disease Smoking159 Poor Nutrition Renal disease Lung disease/hypoxia Environmental agents Endocrine disorders Previous history of IUGR Uterine-placental Uterine-placental dysfunction Placental infarct Chronic abruption Multiple gestation/twin transfusion syndrome Confined placental mosaicism Fetal Chromosome abnormalities Confined placental mosaicism Anomalies Skeletal dysplasias Multiple anomaly syndromes aarskog Ataxia-Telangiectasia Syndrome Bloom Brachmann-de Lange Charge Coffin-Siris Dubowitz Fanconi Johansen-Blizzard Neu-Laxova syndrome Noonan Pena-Shokier Roberts Russel-Silver Seckel Smith-Lemli-Opitz syndrome Williams (Catch 22) Infection Teratogens 12 Abnormal Fetal Growth tory of SGA fetuses is a risk factor for preeclampsia.75 Table 7 presents risk factors for development of IUGR. Underlying uterine-placental dysfunction is a commonly evoked cause for otherwise unexplained fetal IUGR. Uterine-placental dysfunction has been correlated with a range of pathological findings including smaller placentas, increase in the thickness of tertiary-stem villi vessel wall, and decrease in lumen circumference. Uterine-placental dysfunction produces fetal hypoxia, which results in subnormal growth, oligohydramnios, and alterations in blood flow.76 IUGR may be the primary, or in some cases the only sonographic evidence of underlying fetal anomalies. Early onset IUGR is a common manifestation of major chromosome abnormalities, particularly trisomies 18 and 13, and triploidy.77,78 Other chromosomal anomalies or genetic syndromes may exhibit growth delay as a dominant feature. Chromosome abnormalities confined to the placenta (confined placental mosaicism) may also present with IUGR and affected pregnancies are also at higher risk for fetal death.79 Abnormal growth and development has also been associated with disturbed genomic imprinting (expression of genes depending on whether they are located on the maternal or on the paternal chromosome). This has lead to the suggestion that the genomic imprinting has evolved as a mechanism to regulate embryonic and fetal growth.80 Diagnosis The primary sonographic means for detecting SGA fetuses is demonstration of estimated fetal weight to be less than a discriminatory level, commonly set as the 10th percentile. Because estimated fetal weight is strongly influenced by AC, it is important to obtain accurate and consistent measurement of the AC whenever growth disturbances are suspected. Small AC percentiles have been found to be a sensitive marker for IUGR. The small AC measurement may reflect a reduction in size of the liver or other intraabdominal organs, reduced amounts of fat, or possibly an elevated diaphragm because of poor lung growth.81 Symmetric Versus Asymmetric IUGR “Symmetric” IUGR has been used to describe a growth pattern when all biometric measurements appear affected to the same degree, whereas “asymmetric” IUGR has been used to characterize a smaller abdominal circumference compared to other growth parameters. Asymmetric IUGR would then show abnormal ratios such as the HC/AC ratio or FL/AC ratio.82 When first introduced, the term symmetric IUGR was suggested as more likely to reflect underlying fetal condition including aneuploidy, whereas asymmetric IUGR supposedly reflected underlying uterine-placental dysfunction. However, these assumptions have proved to be largely false. Asymmetric IUGR was more likely to be associated with a major fetal anomaly in one study,83 may be seen with aneuploidy (for example, triploidy), and present as early as symmetric IUGR.84 Fetuses with symmetric and asymmetric IUGR also show a similar degree of acid-base impairment.85 The FL/AC ratio has Table 7. Risk Factors for the Development of IUGR. Percent Difference in Estimated Fetal Weight and Birth Weight Associated With Various Maternal and Fetal Characteristics by Gestational Age Mean Gestational Age Characteristics 18 wk 25 wk 31 wk 36 wk 40 wk (birth) Black v white Female v male Cigarettes, ⬎20 vs none Previous low birth weight vs none Height, ⬍157 cm v ⬎167 cm Body mass index, ⬍19.5 v ⬎26 Weight gain, ⬍8 kg v ⬎16 kg Hypertension v none NS ⫺9.2° NS NS NS NS NS NS NS ⫺2.6° NS NS NS ⫺3.6° ⫺3.6° NS NS ⫺1.4° NS NS ⫺3.3° ⫺3.8° ⫺3.8° NS ⫺4.3* ⫺3.2* ⫺5.1* ⫺2.8° ⫺4.4* ⫺6.7* ⫺5.0* NS ⫺4.9* ⫺4.6* ⫺6.2* ⫺3.6* ⫺5.9* ⫺8.8* ⫺7.5* ⫺4.3° Data from Goldenberg RL, Davis RV, Clizer SN, et al: Maternal risk factors and their influence on fetal anthropometric measurements. Am J Obstet Gynecol 168:1197-1205, 1993. Nyberg, Abuhamad, and Ville also been found to be useful for prediction of IUGR.86 Despite these arguments, it is worthwhile to compare the pattern of fetal biometry. Low weight to length ratio is correlated with perinatal morbidity, even in infants not small for gestational age.87 This may reflect fetuses who are compromised but whose weight does not fall below the 10th percentile. Dashe et al83 also found that fetuses with asymmetric SGA are at increased risk for intrapartum and neonatal complications. Fetuses with asymmetric IUGR were more likely to have pregnancy-induced hypertension at or before 32 weeks (7% v 1%), and cesarean delivery for nonreassuring fetal heart (15% v 3%, P ⬍ .001) compared to symmetric IUGR. They were also more likely to have adverse neonatal outcome (14% v 5%, P ⫽ .001) including respiratory distress, intraventricular hemorrhage, sepsis, or neonatal death compared to appropriate for gestational age (AGA) fetuses. In contrast, symmetric SGA infants were not at increased risk. Disproportionately small HC is also important to identify and, when severe, may indicate microcephaly. Microcephaly is typically diagnosed when the HC is 3 SDs below the mean for gestational age.88 The causes of microcephaly are diverse. Among these, cocaine exposure has been associated with microcephaly. Newborns exposed to a high levels of cocaine exhibit asymmetric growth restriction in which the HC is disproportionately smaller than would be predicted from the birth weight (head wasting). The deficit in head size associated with cocaine exposure may reflect the effects of a specific central nervous system insult that interferes with prenatal brain growth.89 Serial Ultrasound Examinations Dynamic evaluation of fetal growth with serial ultrasound is more important than a single examination when fetal measurements are below the 10th percentile. This is true irrespective of the methods used including cross-sectional or longitudinal growth charts, customized growth charts or predicted fetal growth. The optimal measurement interval in small fetuses to combine an acceptable technical error and useful clinical data seems to be around 10 days to overcome intra- and inter-observer variabilities.90 13 However, longer time intervals will more accurately reflect fetal growth in low-risk patients.91 Using 2 or more ultrasounds during the third trimester, Smith-Bindman et al92 found that subnormal fetal growth was associated with a 3.9 times the risk of a birth weight less than 2,500 g, 17.7 times the risk of a birth weight less than the 3rd percentile, 2.3 times the risk of preterm birth, 2.6 times the risk of a prolonged hospitalization for the newborn, and 3.6 times the risk of admission to the neonatal intensive care unit. For each outcome, inadequate growth on serial examinations identified more fetuses with poor birth outcomes than low estimated fetal weight from a single examination. These authors conclude that serial ultrasounds can detect inadequate growth and fetuses at risk of poor outcomes, even when GA is unknown. On the other hand, Williams and Nwebube93 found that a single measurement of the fetal AC made within 1 week prior to delivery was better than assessment of serial examinations in the third trimester for detecting patients who require cesarean delivery for fetal distress. Other Ultrasound Measures of IUGR A number of other abnormal morphologic measurements or ratios may be used in an attempt to identify fetuses affected with IUGR. The most interesting measurements are those of internal organs such as the brain, kidneys, and liver. The kidneys are affected in fetuses with IUGR and this probably explains oligohydramnios in these patients. Silver et al94 found that IUGR fetuses had significantly smaller renal volumes than control fetuses, but no difference in renal artery Doppler measurements. Smaller renal volumes may correlate with oligonephropathy and this may help to explain the association between IUGR and an increased risk of developing hypertension and related cardiovascular diseases among adults.94 Boito et al95 used three-dimensional ultrasound to evaluate liver size in growth disturbances. Among normally grown fetuses, they found that the mean liver volume was 9.7 mL (SD 4.4) at 20 weeks and 96.4 mL (SD 8.2) at 36 weeks of gestation. In a small group of fetuses affected with growth restriction, the the liver volume was 45% of expected whereas the AC was 82% of expected. Although this difference was 14 Abnormal Fetal Growth not statistically significant, it suggests that measurement of hepatic volume may be more sensitive than measurement of AC for evaluating fetuses with growth restriction. In a subsequent study, Boito et al95 found that fetuses found to be SGA had a higher brain to liver volume ratio than control fetuses (5.9 v 3.4, P ⬍ .001). Furthermore, the brain/liver volume ratio was inversely related umbilical venous blood flow. Other Parameters of Assessing Fetal Well Being Measurements of fetal biometry can help identify fetuses who are SGA, but cannot necessarily distinguish healthy from compromised fetuses. Therefore, in the setting of a SGA fetus, it is important to correlate fetal size with other correlates of fetal health. Available methods for evaluating fetal well being include cardiotography (CTG), amniotic fluid assessment with or without other components of the biophysical profile, and Doppler studies.97-99 These methods provide a wealth of information regarding fetal well being that can help to identify compromised fetuses. Although these tests are usually interpreted separately, integration of these tests could provide a better overall assessment of fetal health. Scoring systems that incorporate sonographic estimates of fetal weight, amniotic fluid assessment, and clinical parameters have been devised.99,100 Cardiotocography, also known as the nonstress test, is one of the more established methods of fetal surveillance. During cardiotocography, the physician looks for heart rate variability as a sign of fetal well-being. Heart rate variability is the final result of the rhythmic, integrated activity of autonomic neurons generated by organized cardiorespiratory reflexes.101 In growth restricted fetuses, higher baseline rates, decreased long- and short-term variability, and delayed maturation of reactivity is seen in heart rate tracings.102,103 Some studies suggest that replacing standard CTG with computer analysis further improves the prediction of fetal distress and mortality in IUGR fetuses.104 Unaided visual analyses of fetal heart rate records have been shown to have limited reliability and reproducibility.105,106 Furthermore, the presence of overtly abnormal patterns of fetal heart rate tracings represents late signs of fetal deteriora- tion.107,108 Relying on unaided visual analysis of cardiotocography as the only test of fetal surveillance in growth restricted fetuses have come under criticism as it represents late signs of fetal deterioration and thus its sole use may not optimize long-term outcome of these pregnancies. The biophysical profile (BPP) has been correlated with fetal pH, perinatal morbidity and fetal mortality in cases of IUGR.109 Lower BPP scores have associated with low arterial pH, low Apgar scores and increased rate of cesarean sections in growth restricted fetus.110 The biophysical profile has also been shown to better correlate with fetal well being than fetal heart rate tracing among patients in labor.111 In nearly all cases of severe IUGR, abnormal BPP scores occur after or simultaneously with deterioration of arterial and venous flow patterns on Doppler studies. Therefore, addition of Doppler studies should improve the performance of the biophysical score in the detection of fetal distress.112 The classic BPP evaluates five characteristics: fetal movement, tone, breathing, heart reactivity, and amniotic fluid volume estimation. The basis of the BPP is that components of the BPP follow a predictable pattern secondary to hypoxia. Loss of fetal breathing movements is the most sensitive, but also the least specific, of the parameters. Further hypoxia may reduce fetal movements and, in the most severe cases, affect fetal tone. Low amniotic fluid volume reflects chronic hypoxia whereas the other parameters reflect more acute changes. Low amniotic fluid is usually defined as an amniotic fluid index of 5 or less, although various criteria have been used.113 A number of modifications to the standard BPP have been proposed. The most common modification is to omit heart reactivity and to evaluate that separately as the nonstress test.114 The rapid BPP has been defined as amniotic fluid assessment and sound-provoked fetal movement. It has been found to be an effective predictor of intrapartum fetal distress in highrisk pregnancies and appears to be more effective than nonstress tests.115 Doppler ultrasound can provide important physiologic information of altered flow states, either in the fetal-placental or the uterine-placental circulations. The umbilical artery is the most common site of sampling with duplex Doppler. It reflects the umbilical-placental cir- Nyberg, Abuhamad, and Ville culation from the fetal side. Abnormal waveforms patterns may be seen with IUGR and placental dysfunction. Doppler may also be used to interrogate a variety of other sites of the fetal circulation, including the middle cerebral artery, aorta, and splenic artery, among others.116 A comparison of arterial resistance of the umbilical and cerebral circulations has been referred to as the cerebroplacental Doppler ratio. Although this ratio varies somewhat during pregnancy, reflecting the quadratic relationship of resistance observed of the middle cerebral artery with gestational age,117 it almost always exceeds 1 throughout pregnancy. Reversal of this normal relationship may be seen with the “brain sparing” effect. A number of cross-sectional and longitudinal studies have highlighted the fetal cardiovascular adaptation to hypoxemia and the progressive stages of such adaptation.118-123 Findings from these studies suggest that arterial Doppler is the first Doppler abnormality to be seen. Venous Doppler abnormalities, which reflect fetal cardiac dyfunction, are late signs of fetal adaptation and are commonly associated with the presence fetal acidemia. Overt abnormalities of fetal heart tracing and loss of biophysical parameters appear to follow venous Doppler changes in most growth restricted fetuses. Use of Doppler ultrasound has been shown to improve outcome in high-risk pregnancies.124 Clinical management based on information obtained from umbilical artery Doppler velocimetry prior to 32 weeks may result in decreased perinatal mortality and lower rates of obstetric interventions.125 Although morphometric measurements are, not surprisingly, more accurate than Doppler studies for identification of SGA fetuses,126 Doppler studies have found to be useful in prediction of adverse outcome among SGA fetuses.127 Uterine artery Doppler reflects the uterineplacenta circulation from the maternal side. Abnormal placentation and trophoblastic invasion may result in abnormal waveform patterns of the uterine arteries, and predict future development of pre-eclampsia and IUGR. Uterine artery Doppler has the potential to identify patients in the “pre-disease” condition who are at risk for fetal growth delay and adverse outcome.128 Uterine artery Doppler has been shown to be particularly effective in patients at risk of developing 15 hypertension when used during the second trimester. Abnormal uterine artery Doppler waveforms near term have also been associated with an increased risk of adverse outcome among growth restricted fetuses.129 Macrosomia Large-for-gestational age (LGA) is defined by an estimated fetal weight greater than the 90th percentile. Neonatal macrosomia is defined in absolute terms as birth weight greater than 4,500 g; old charts used 4,000 g but physiological birth weights have increased over the years. As expected, the prevalence of macrosomia varies widely between countries. Because of a higher risk of fetal mortality and morbidity, accurate prediction of macrosomia is a public health problem which answer partly relies on fetal ultrasound examination. However, there are 3 problems in screening for macrosomia: the sonographic diagnosis of macrosomia is not reliable, 90% of macrosomic babies will not suffer any complication, and finally prevention of perinatal morbidity and mortality would imply a 10% increase in the cesarean section rate and its maternal morbidity. Risk Factors Risk factors are well established with a good sensitivity but are not specific since most women at risk will deliver babies of normal weight. The main risk factors are grouped under the acronym “DOPE,” standing for diabetes, obesity, postdates, excessive fetal weight or maternal weight gain sequence. Genetically driven excessive growth can be seen in a number of conditions (Table 8). An excessive prenatal growth rate is usually maintained throughout the pregnancy. Precise diagnosis is often difficult to ascertain and relies on subtle differences; the prognosis is also extremely difficult to ascertain antenatally and in the neonatal period.130 Diagnosis There are numerous mathematical formulae and indices developed to predict fetal macrosomia.131-137 Simple formulae for estimating fetal weight may do just as well as complex ones.138,139 Nearly all formulas include the AC because it accurately reflects fetal girth. 16 Abnormal Fetal Growth Table 8. Associations With Excessive Fetal Growth (Macrosomia) Pertinent features in early Overgrowth syndromes Excessive growth of prenatal Onset Accelerated osseous maturation Developmental delay Mental retardation Poor co-ordination Learning difficulties Hoarse, abnormal cry Dysarthric speech Dilated ventricles and cavum septiPellucidi Craniofacial features Macrocephaly Hypertelorism Large ears Down-slanting palpebral fissures Relative micrognathia Limbs Campto(clino)-dactyly Prominent finger pads Flared metaphases Increased risk for malignancy Gene locus Weaver Sotos Marshall-Smith Beckwith-Widemann Simpson-Golabi-Behmel ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹ ⫹ ⫹ No Speech ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹ ⫹ ? ⫹⫹ ? ? ⫹ ⫹ ⫹⫹ ⫹⫹ ⫹ ⫹ ⫹⫹ ⫹⫹ 11p15.5 ⫹ Xp26 ⫹ Data from Ville Y, Nyberg DA, in Nyberg DA, McGahan JC, Pretorius DH, et al: Growth, Doppler, and Fetal Assessment, Diagnostic Imaging of Fetal Anomalies, Lippincott and Williams, 2003. Most studies now define macrosomia as estimated weight greater than 4,500 g. However, some studies have used 4,500 g among nondiabetics but 4,000 g among diabetic women since they are at greater risk of fetal macrosomia.140 The mean sonographic error in estimating fetal weight is higher with macrosomic fetuses, reaching 15% at term compared to less than 10% for normal size fetuses. Field et al135 found that regardless of maternal size, almost half of the weight predictions were within 5% of the actual birth weight Approximately 50% to 70% of estimated weights fall within than 10% of the actual birth weight encompassing the cut-off of 4,000 g in 95% of the cases when the estimated birth weight is equal or superior to 4,000 g.133-137 On the other hand, maternal diabetes probably does not change the accuracy of the measurements, although some authors suggest that prediction of fetal weight is worse in diabetic pregnancies.141 In nondiabetic patients, the addition of a glucose challenge test at 24 to 28 weeks showed limited ability to improve sonographic prediction of fetal macrosomia.142 Measurement of AC alone may identify macrosomic fetuses. Gilby et al143 found that if the AC was ⬍35 cm, the risk of infant birth weights ⬎4,500 g was ⬍1%. On the other hand, if the AC is ⬎ or ⫽ 38 cm, the risk was 37% (37/99), and ⬎50% of these infants were identified (37/69 or 53.6%). Holcomb et al144 suggest that the abdominal circumference percentile is useful and should be reported, in addition to estimated weight percentile, in fetuses who are large for GA. Other measurements may be obtained to help detect macrosomia and complications of macrosomia, including soft tissue measurements. However, measurements of soft tissue do not appear to be superior to clinical or sonographic predictions in identifying fetuses with weights of at least 4,000 g.145 Ultrasound is not considered to be specific enough to predict shoulder dystocia. A few studies using ultrasound or even magnetic resonance imaging have been encouraging.146-148 However, Nyberg, Abuhamad, and Ville the sensitivity and specificity of are unlikely to be over 40% and 75% respectively, which would mean to perform a cesarean section in 25% of the patients to avoid only 40% of all shoulder dystocias.149 A number of studies have concluded that clinical examination works just as well as ultrasound to predict birth weight at term, especially when it is above 4,500 g.150-154 A two-step clinical and sonographic approach does not perform better since the sensitivity is 17% and the positive predictive value is only 36% for estimated birth weight of ⬎4,000 g.150 The predictive value of a LGA fetus is further increased when polyhydramnios is also present. Sohaey et al155 reported that 28% of fetus with polyhydramnios had birth weights at the 90th percentile or greater. Conversely, the combination of oligohydramnios and a fetal weight estimate below the 90th percentile virtually excludes the possibility of LGA.156 The origin for polyhydramnios among largefor-gestational age fetuses remains unclear. Maternal diabetes is not independently associated with polyhydramnios, after accounting for macrosomia.157 Some have suggested polyhydramnios may reflect increased renal vascular flow, whereas others suggest it is secondary to bulk flow of water across the surface of the fetus, umbilical cord, placenta and membranes. Larger fetuses with larger lung volumes and placental surface areas would be expected to produce greater amounts of amniotic fluid. Although one might also expect a relationship between the severity of polyhydramnios and birth weight, no direct correlation has been found.157,158 Conclusions A primary role of obstetric ultrasound is determining GA and assessing fetal growth. 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