Ultrasound in assessment of fetal growth disorders: is there a role for subcutaneous measurements?

A brief review of normal human development may be helpful in understanding fetal and newborn fat accretion and in setting the stage for future ultrasound studies. One of the unique characteristics of human development includes the growth of a very large brain and the deposition of a very large amount of white fat tissue3, 4. The accretion of fat represents over half of the calories accrued by the fetus from 27 to 40 weeks' gestation and approximately 90% of the caloric accretion in the last few weeks of pregnancy. Sparks et al.4 have also delineated the striking accumulation of white fat depots in the near-term and term fetus. This pattern of fat accretion for the human fetus has many clinical implications. First, fat deposition is particularly important as it applies to diabetes in pregnancy. Second, it means that the recognition of IUGR is far more likely to be made in late gestation, when a decrease in fat stores is clinically obvious. In earlier gestation (e.g. 26–30 weeks) there are few fat depots present even in normally grown preterm infants. This makes recognition of IUGR by fat assessment more difficult. This point is emphasized by early studies by Ogata et al.5 utilizing serial ultrasound measurements of fetal abdominal circumference in diabetic pregnancies, which brought out the fact that a clear-cut deviation from normal growth was not apparent until > 30 weeks' gestation. For diabetic pregnancies, whether insulin-dependent or gestational diabetics, macrosomia is the most frequent problem encountered and these large infants have significantly increased fat stores compared to other LGA babies6. Many researchers have sought to characterize the normal variation in fetal growth. Prior to the advances in ultrasound, these investigators have been traditionally limited to studying the neonate. In a benchmark study, Lubchenco et al.7 compared the relationship of weight to length in over 4700 fetuses born between 26 and 42 weeks' gestation in Colorado from 1948 to 1961. In this study, the ratio of weight to length, according to Rohrer's formula8 of weight × 100/length3, was then calculated. Rohrer's formula is now commonly referred to as the ponderal index, which is a measure of neonatal corpulence or ‘scrawniness’. The ponderal indices were then plotted across the aforementioned gestational ages to create a nomogram. For many years, the ponderal index and Lubchenco's nomogram have been of value in determining aberrations in fetal growth. While these are valuable methods to generally describe the differences in nutritional status of a neonate relative to gestational peers, they are limited in their ability to explain why these differences might exist. Others have sought to examine specific neonatal compartments, such as the deposition of adipose tissue, in order to more precisely detail the differences in weights and composition at birth. Dauncey et al.9 developed a technique for estimating neonatal fat, which assumes that the fetal head is a sphere without fat. Additionally, the trunk and limbs are viewed as cylinders covered with a fat layer. The triceps skinfold thickness is used to estimate the fat thickness of the limbs, whereas, the subscapular skinfold thickness estimates the trunk. For each skinfold thickness, the measurement is reduced by 2 mm to account for the thickness of the dermis as previously described by Hammond10. The circumference of the upper limb is measured at the upper arm, whereas the trunk circumference is the circumference of the chest. The circumference of the lower limb is an average of the mid-thigh circumference and the calf circumference. Fat volume is then calculated by multiplying the length × circumference × skinfold thickness estimates of the fat layer. The sum of the fat volumes is multiplied by the density of human fat tissue (0.9) and then subtracted from the birth weight to determine the lean body mass. This technique of measuring neonatal fat mass and, thereby, lean body mass became a key component of future neonatal studies. The Dauncey technique estimated that a full-term healthy neonate contains approximately 11–13% fat. There have been several studies using Dauncey's and alternative measuring techniques which have shown very similar fat content11, 12. A major assumption of the Dauncey technique, however, is that the triceps and subscapular skinfold thickness are an adequate approximation of the subcutaneous layer thickness in infants. In fact, a study by Kabir and Forsum13 cast doubt on the technique developed by Dauncey. Specifically, they were critical of the Dauncey technique because there have been no studies which confirm his triceps and subscapular skinfold thickness assumption. Also, similar caliper measurements in adults and children have been shown to often overestimate the adipose tissue in people with thick skinfolds14, 15. Additionally, Kabir and Forsum's findings regarding adipose tissue composition suggested that the density of neonatal adipose tissue as described by Dauncey needs to be modified. Dauncey estimated the density of fat as 0.9 g/cm3. In studies of adult women16, the density of adipose tissue has been shown to be 0.77 g/cm3. It is unknown whether the density of fat changes from the neonatal period to adulthood. Though the ponderal index is considered a useful measure of neonatal corpulence, it is a poor predictor of the fetal percent body fat. Catalano et al.17 performed anthropometric measurements on 188 neonates from uncomplicated singleton term pregnancies in Vermont within 24 h of delivery to estimate the lean body mass and body fat. The objective was to determine if body composition analysis could explain the variances in normal birth weight. The measurements included weight, length, triceps and subscapular skinfold thickness, head, chest, abdomen and limb length measurements. Body fat was estimated according to the aforementioned Dauncey technique. A significant linear correlation was noted between birth weight and lean body mass, fat mass and ponderal index. The results showed that the variance seen in fetal weight could largely be explained by the neonatal fat mass. Though neonatal fat mass only constitutes 14% of birth weight, it explains approximately 46% of its variance. Conversely, the ponderal index, which is often used as an indicator of a fetal nutritional abnormality, explained only 22% of the variance in body weight. Copper et al.18 further demonstrated the limitations of the ponderal index relative to the body size differences of full-term male and female infants. In their prospective study from 1993, they measured triceps, subscapular and thigh skinfold thickness on 1205 newborns born from 1985 to 1988. Female infants were significantly lighter with shorter long bone or crown-to-heel lengths and smaller circumferences than their male counterparts. At the three sites studied, however, female infants had a significantly greater mean skinfold thickness. The calculated values for the ponderal index were nearly identical. The ponderal index, therefore, does not reflect the gender differences in fat deposition. As ultrasound technology and two-dimensional (2D) resolution advanced rapidly, investigators became interested in extending these newborn studies back into intrauterine life. Over the past 20 years, in utero measurement of the subcutaneous tissue and lean mass has also evolved. Several investigators have evaluated the subcutaneous tissue of the arms, legs and abdomen. Less attention has been focused on measuring the subcutaneous tissue of the face and buttocks. There are certain significant advances in the understanding and technique of measuring the subcutaneous tissue by ultrasound that are worth noting. The subcutaneous tissue of the arm and leg is the most extensively studied of the subcutaneous compartments. In 1985, Jeanty et al.19 were one of the first groups to describe measurement of the subcutaneous tissue in the extremities. Limb volume is calculated using measurements of the subcutaneous tissues of the arm and leg. In this technique, transverse and anteroposterior arm thicknesses are measured. In a cross-sectional view of the limb, the subcutaneous tissue thickness is measured as the distance between the hypoechogenic area of muscle and the amniotic fluid. Multiple diameters are obtained. Additionally, the thickness is measured in a transverse section from one edge of the bright echo to the other. Using a complex equation, the arm perimeter and volume are calculated. In determining the arm perimeter, a circle was designated as the geometric model rather than an ellipse as the ellipse was difficult to compute and did not change the coefficient of correlation. Limb volume was strongly correlated with gestational age. Unfortunately, the limits of ultrasound technology at the time made accurate measurements of small distances very difficult. Subcutaneous tissue thickness, therefore, was not a good predictor of intrauterine growth except in cases such as macrosomia in which the deposition of adipose tissue is greatly exaggerated. Around the same time, Vintzileos et al.20 described the normal range of fetal thigh and fetal calf circumferences for each week of normal pregnancy after 20 weeks' gestation. Fetal thigh and calf circumferences were measured according to a technique developed by Deter et al.21. According to Deter's technique, circumference measurements of the thigh are made on a cross-section at the midpoint of the femur, where the bone profile changes in shape from a polygon to a circle. Fetal calf measurements are made just below the knee. The diameter of the limb is measured in two dimensions from the outer hyperechogenic border of the limb to the opposite outer hyperechogenic border. Using the assumption that the limb is a circle, the circumference is then calculated using the formula ((D1 + D2) × 1.57). Vintzileos then used these circumference measurements to create the ratios of fetal femur length to thigh circumference and fetal tibia length to calf circumference. In normally grown fetuses, these ratios are unchanged from 20 weeks' gestation through term. In detecting SGA there was a positive predictive value of 83.3% for the femur length to thigh circumference and tibia length to calf circumference ratios. When LGA fetuses were measured, the ratios became abnormal several weeks prior to the fetal weight exceeding the 95th percentile. Additionally, the positive predictive value was 100% for the detection of macrosomia. In 1997, Bernstein et al.22 developed another method to assess fetal limb fat by ultrasound. Subcutaneous fat and lean body mass areas are measured on axial ultrasound images of the mid-upper arm and mid-upper leg. A longitudinal view of the long bone and extremity is obtained with an angle of 0° to the transducer. The transducer is then rotated 90° to obtain the axial view of the extremity. The fat area is measured by taking the total cross-sectional limb area and subtracting the central lean area that consists of muscle and bone (Figure 1a and 1b). The fat area and lean body in the single plane described above are assumed to approximate the fat mass and lean body mass in the fetus. Bernstein et al. utilized this method in a prospective study to determine fat and lean body mass growth in 36 fetuses of non-smoking women with a normal prepregnancy body mass index (BMI) based on maternal age. There were significant correlations between ultrasound estimates of fetal fat and lean body mass and the neonatal estimates. The ultrasound measurements revealed a linear increase in lean body mass for both the mid-thigh and the mid-arm between 19 and 40 weeks' gestation. The lean body mass increased by five-fold with gestational age being the only significant independent variable. The cross-sectional subcutaneous fat measurements demonstrated a 10-fold increase in the second half of gestation. Interestingly, there was a significant positive relationship with the maternal age. A study by our group in 2001 similarly utilized the Bernstein technique to explain the differences in birth weight observed between moderately high altitude and sea level23. We found that the lower weight in Denver (1600 m) than those in Milan (40 m) could be accounted for by differences in subcutaneous fat whereas lean mass was similar between the two populations. Both studies demonstrated good intra- and interobserver variabilities. (a) Scheme of an ultrasound axial view of the extremity (here the thigh or proximal arm) demonstrating the fetal subcutaneous (SQ) and lean tissues and how the areas are calculated. SQ area = total cross-sectional area—lean mass area. (b) Ultrasound axial view of the fetal thigh with outlines of the subcutaneous and lean tissue. B, bone; M, muscle; S, subcutaneous tissue. In follow-up to the studies assessing fetal fat and lean mass accretion throughout the normal pregnancy, investigators have focused on deviant fetal growth. In assessing fetal growth abnormalities, the abdominal circumference is considered by many to be the most sensitive indicator. In 1992, Hill et al.24 measured the abdominal subcutaneous tissue thickness, in addition to mid-thigh and mid-calf subcutaneous tissue thickness, in order to distinguish abnormalities of fetal growth. Hill measured the subcutaneous tissue thickness 2 cm lateral to the umbilical cord insertion at the same level as that normally determined for the abdominal circumference (Figure 2). Normal fetuses of 244 women were measured from 15 to 42 weeks' gestation to serve as a control. In order to assess the intraobserver variability, the same sonographer performed the measurement at the beginning and end of the exam, but was blinded to the numerical value. Interobserver variability was assessed by two independent examiners. The mean difference between measurements for both the intra- and interobserver variability was essentially zero. Measurements of the abdominal subcutaneous tissue thickness were unable to predict growth disturbances for either IUGR or LGA fetuses. The assumption is that fetuses deposit subcutaneous tissue in a uniform fashion. One fetus may deposit fat 2 cm lateral to the cord insertion, whereas another fetus may be depositing more fat 3 cm lateral to the insertion. Single-point measurement might overlook any differences that exist between fetuses. Axial ultrasound view of the fetal abdomen demonstrating the technique by Hill et al.24 of measuring 2 cm lateral to the umbilical cord insertion site at which point subcutaneous tissue is measured. In 1997, Petrikovsky et al.25 performed similar measurements as Hill et al. to determine if abdominal subcutaneous tissue thickness could predict fetal macrosomia. These authors measured 133 term fetuses, all of which were delivered within 72 h of measurement. Rather than measuring the thickness 2 cm lateral to the umbilical cord insertion, the subcutaneous tissue thickness was measured at its widest point in the anterior third of the abdominal circumference on an axial view (Figure 3). In this technique, the calipers are placed at the outer and inner edges of the subcutaneous layer. Unlike the results obtained by Hill, Petrikovsky determined these sonographic measurements are useful for ruling out macrosomia. The positive predictive value for macrosomia increased as the amount of abdominal subcutaneous tissue increased. When a cut-off of ≥ 11 mm was used, the positive predictive value ranged from 75.5% to 93.7%. For thicknesses < 11 mm, the positive predictive value for macrosomia was always less than 60%. In 1999, Gardeil et al.26 hypothesized that prenatal measurement of fetal abdominal fat could predict growth restriction in fetuses. This prospective study involved serial ultrasound scans on 137 women in Ireland with singleton pregnancies. The fat mass of the abdomen was determined by measuring the thickness of the anterior abdominal subcutaneous tissue, anterior to the margins of the ribs, on the same axial image on which the abdominal circumference is obtained. Gardeil determined that an infant with subcutaneous fat of < 5 mm was five times more likely to have a birth weight below the 10th percentile than an infant with > 5 mm of subcutaneous fat. In these infants with a subcutaneous fat measurement of < 5 mm, there was a significantly higher incidence of neonatal morbidity. Axial ultrasound image of the abdomen showing measurement of the subcutaneous fat. (a) Standard view; (b) enlarged view. An area that has not been extensively studied is the adipose tissue present in the fetal face, specifically the cheeks. In 1991, Abramowicz et al.27 described their technique for measuring the cheek-to-cheek diameter. The premise for developing nomograms for this particular measurement is based on the assumption that poorly nourished individuals have sunken cheeks, whereas people with increased weight gain have fuller cheeks. Perhaps adipose deposition in the fetal face might also reflect nutritional status. Abramowicz described obtaining a coronal view of the fetal face at the level of the nostrils and lips. At this level, the distance between the widest points on each cheek is measured (Figure 4a). Because this view is occasionally difficult to obtain, the authors recommend measuring the distance from the proximal cheek to the middle of the mouth if the complete cheek-to-cheek view cannot be visualized (Figure 4b). The cheek-to-mouth value is then multiplied by two in order to approximate the cheek-to-cheek diameter. Abramowicz determined that the cheek-to-cheek diameter grows linearly from 20 to 41 weeks' gestation, with a mean of 3 cm at 20 weeks increasing to 7.1 cm at 41 weeks. Additionally, the cheek-to-cheek diameter/biparietal diameter (BPD) ratio was developed to describe differences observed in growth-restricted and macrosomic fetuses. The cheek-to-cheek diameter/BPD ratio is fairly consistent throughout gestation in normally grown fetuses. Growth-restricted fetuses had lower ratios because of the decreased deposition of adipose tissue28. Macrosomic fetuses of diabetic mothers had increased ratios above normal gestation due to increased fat deposition. Interestingly, in LGA fetuses of non-diabetic mothers, the ratios of cheek-to-cheek diameter/BPD are not statistically different from those observed in appropriately grown fetuses. (a) Axial view through the face showing the cheek-to-cheek measurement. (b) Axial view through the face measuring the distance from the proximal cheek to the middle of the mouth when the cheek-to-cheek view cannot be visualized. Finally, in addition to the fetal cheeks, another area that has been minimally studied involves the deposition of fat in the fetal buttocks. Matsumoto et al.29 performed a three-dimensional (3D) evaluation of fetal soft tissue on 52 fetuses from 29 to 41 weeks' gestation within 1 week of delivery. They created a fetal nutrition score involving the amount of subcutaneous tissue present at the face, ribs and buttocks. Unlike other investigators, however, Matsumoto did not measure subcutaneous tissue these were in which the fetus is a score between 1 fat to 5 fat for each of the above For for the fetal a fetus the score of 1 if the noted to no no or and to 5 for with a then a nutritional score on the neonate. This study found a linear correlation between the fetal nutrition score and the neonatal nutritional This study is of not from the of but because it includes an assessment of the adipose tissue in the which is an area that fat tissue. A review of the revealed no other studies in which the fetal were measured or evaluated by ultrasound. understanding of the measurement of subcutaneous fat and its clinical value is in its There are several in body composition that to be this area be viewed with greater First, our understanding of which significant of fetal adipose tissue needs to be all of the above and have significant fat there any Second, from the to one that there is a linear deposition of fat in each 20 weeks' gestation until term. It is however, if any fat at a greater than the other in normal or if of fat is less when nutritional to the fetus is there needs to be both and the for each Over the past 20 years, there have been techniques for measuring the subcutaneous tissue, for the limbs and abdomen. A of however, has not been In technique, a be made as to whether length of limb, or needs to be included that a volume of subcutaneous tissue is obtained. most studies subcutaneous area as a measure of fat a single image the fat deposition throughout the fat fat volume and fat mass measurements One might that fat a and fat a might with one fat mass, which on ultrasound measure of may be more poorly Perhaps fat assessment by volume assessment of both fat and lean mass. Additionally, the amount of fat in the fetal face and needs to be studied in greater is to determine the density of fetal fat that fat mass may be calculated. there are values in the In this one if fat density is in all or whether differences exist between and maternal In of fetal fat stores could on the nutritional status of the with to in the diabetic and and in the IUGR fetus. or not subcutaneous and lean mass measurements are helpful in the fetus that is small for normal or from the fetus that is small and at for of and IUGR has not been determined and an area for even if subcutaneous measurements out to be in this it is to that the of subcutaneous fat measurements likely be most useful in the half of the third At this of pregnancy, delivery for the IUGR fetus are less these fetuses generally the SGA fetus has normal subcutaneous mass and normal umbilical this may a pregnancy that to the estimated of the time and of serial as as the of or for the small fetus at for IUGR in the early third subcutaneous measurements likely be less useful and it may be that of of subcutaneous measurements in the fetus of the diabetic may a to assess and for The of ultrasound for assessment of fat and lean mass largely but may useful in the of those pregnancies with a fetal growth