- Email: [email protected]
Differential growth of fetal tissues during the second half of pregnancy
Differential growth of fetal tissues during the second half of pregnancy Ira M. Bernstein, MD, a Michael I. Goran, Phi), b Saeid B. Amini, MBA, PhD, r and Patrick M. Catalano, M D c
Burlington, Vermont, Birmingham, Alabama, and Cleveland, Ohio OBJECTIVE: Our purpose was to examine the pattern of growth of both fetal lean body mass incorporating bone, brain, and muscle and subcutaneous fat mass during the course of normal pregnancy. We hypothesized that there are detectable differences in the accretion of fat versus lean body mass. STUDY DESIGN: To establish our method we correlated standardized cross-sectional ultrasonographic images of the fetal extremities with anthropometric assessment of neonatal body composition in 25 subjects. Subsequently 36 nonsmoking women with normal prepregnancy body mass index, normal glucose screening results, and no medical or obstetric complications were recruited. We performed 135 ultrasonographic examinations between 19 and 40 weeks' gestation (mean 3.8 scans per fetus, range 2 to 6) at 4-week intervals. Lean body mass measures included biparietal diameter, head circumference, and femur length. Fetal subcutaneous fat and lean body mass were examined both in the mid upper arm and midthigh by standardized cross-sectional images. All neonates were born between 37 and 42 weeks' gestation and had normal birth weight distribution. Stepwise regression analysis established best-fit equations for fetal measurements obtained ultrasonographically. Independent variables included gestational age, maternal age, weight gain in pregnancy, parity, fetal gender, and maternal prepregnancy weight. RESULTS: Fetal bone growth was best described by a second-order quadratic equation demonstrating deceleration with advancing gestational age (/3 < 0.0001, R2 0.92 to 0.96). A quadratic equation that accelerates with advancing gestation best described lean body mass accretion in the extremities (p < 0 . 0 0 0 1 , R 2 = 0.85 to 0 . 8 6 ) . Fetal fat deposition in the extremities was characterized by an accelerating quadratic equation when plotted against gestational age with maternal age and prepregnancy weight contributing significantly (p < 0.0001, R 2 = 0.80 to 0.81). CONCLUSION: Consistent with our hypothesis, fetal fat and lean body mass demonstrate unique growth profiles. We speculate that, as a result of an accelerated rate of growth in late gestation, the measurement of fetal fat will provide a more sensitive and specific marker of abnormal fetal growth when compared with index values of lean body mass. (Am J Obstet Gynecol 1997;176:28-32.)
Key words: Differential growth, fetal tissues, pregnancy, fetal growth, ultrasonography
Fetal size is most commonly characterized by comparison of ultrasonographically estimated fetal anthropometric parameters (abdominal circumference, biparietal diameter [BPD], femur length with population-based growth charts that establish normal size for each parameter across gestation. The most sensitive of the individual From the Department of Obstetrics and Gynecology, University of Vermont College of Medicine, a the Department of Nutrition Sciences, University of Alabama-Birmingham, b and the Department of Reproductive Biology, Case Western Reserve University at Metrohealth Medical Center.c Supported by a Mead Johnson/American College of Obstetricians and Gynecologists Clinical Research Fellowship (I.M.B.), the University of Vermont Sims Obesity~Nutrition Research Center, and the University of Vermont Clinical Research Center National Institutes of Health grant no. GCRC MO1-RRI09. Receivedfor publication April 11, 1996; revisedJuly 18, 1996; accepted August 14, 1996. Reprints not available from the authors. Copyright 9 1997 by Mosby-Year Book, Inc. 0002-9378/97 $5.00 + 0 6/1/77316 28
fetal parameters for the detection of growth abnormalities is the abdominal circumference. 1-a Estimated fetal weight, which is widely used as an index of fetal size, is generally estimated through a combination of parameters, routinely including abdominal circumference. Estimated fetal weight demonstrates predictive value similar to that of abdominal circumference. 1' 2.4 In the adult fat content correlates most directly with energy stores, and the distinction between fat mass and lean body mass is often used in the nutritional assessment of the individual. In the newborn, fat, although constituting only 12% to 14% of birth weight, has been demonstrated to account for 46% of the variance in neonatal weight. 5 These findings suggest to us the potential usefulness of ultrasonographically generated estimates of fetal fat for the determination and evaluation of fetal growth abnormalities. We therefore sought (1) to develop a method that would allow us to assess fetal fat
Bernstein et al.
Volume 176, Number 1, Part 1 Am J Obstet Gynecol
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Fig. 1. Head area plotted across gestational age (GA). This relationship was best described by following polynomial: Head area = -10,157.5 + 775.3(GA) - 7.7(GA2). Adjusted R 2 = 0.94.
Fig. 2. Abdominal area plotted against gestational age (GA). This relationship was best described by following polynomial: Abdominal area = -7250.1 + 408.2(GA) + 28.8(Maternal age). Adjusted R z = 0.87.
a c c r e t i o n in u t e r o a n d t h e n (2) to d e t e r m i n e the g r o w t h rates of various fetal tissues with a focus o n d i s t i n g u i s h i n g b e t w e e n t h e a c c r e t i o n of fat mass a n d fat-free mass. We h y p o t h e s i z e d t h a t t h e r e w o u l d b e u n i q u e g r o w t h profiles associated with the d e p o s i t i o n o f fetal fat mass relative to l e a n b o d y mass.
o f t h e criteria of C a r p e n t e r a n d Coustan. 1~ All w o m e n were free o f m e d i c a l or obstetric disorders k n o w n to affect fetal growth. I n f o r m e d written c o n s e n t was obt a i n e d in a c c o r d a n c e with t h e University o f V e r m o n t C o m m i t t e e o n H u m a n R e s e a r c h for b o t h s e g m e n t s o f the study. A n A c u s o n ( M o u n t a i n View, Calif.) XP3 u n i t with a 3.5 M H Z c u r v i l i n e a r t r a n s d u c e r was u s e d for u h r a s o n o g r a p h i c e x a m i n a t i o n s . We p e r f o r m e d 135 ultras o n o g r a p h i c e x a m i n a t i o n s b e t w e e n 19 a n d 40 weeks' gestation ( m e a n 3.8 scans p e r fetus, r a n g e 2 to 6) at &week intervals. L e a n b o d y mass m e a s u r e s i n c l u d e d BPD, h e a d circumference, a n d f e m u r length. All p a r a m eters were evaluated by s t a n d a r d i z e d t e c h n i q u e s . 11-13 A b d o m i n a l c i r c u m f e r e n c e a n d a b d o m i n a l area were m e a s u r e d at the a n a t o m i c p l a n e s t a n d a r d i z e d for t h e assessment of t h e a b d o m i n a l circumference. A r e a meas u r e m e n t s o f the fetal h e a d were o b t a i n e d at t h e level o f t h e BPD. L e a n b o d y area a n d fat area in t h e e x t r e m i t i e s were m e a s u r e d as previously o u t l i n e d . All area m e a s u r e m e n t s were automatically calculated by the software p r o g r a m of the A c u s o n XP-3 w h e n t h e p e r i m e t e r estim a t e s o f a m e a s u r e d o b j e c t are e n t e r e d . G e s t a t i o n a l age a s s i g n m e n t was b a s e d o n the n u m b e r o f c o m p l e t e d m e n s t r u a l weeks. In all cases this a g r e e d with a n ultras o n o g r a p h i c e s t i m a t i o n of fetal size o b t a i n e d b e f o r e 20 weeks' gestation. I n t r a o b s e r v e r reliability for area meas u r e m e n t s o f t h e m i d h u m e r u s a n d m i d f e m u r fat a n d lean mass ( i n c l u d i n g b o n e a n d muscle) a n d fetal h e a d a n d a b d o m i n a l area was d e t e r m i n e d in 10 subjects. T h e coefficients o f v a r i a t i o n were calculated o n t h e basis o f area m e a s u r e m e n t s to allow d i r e c t c o m p a r i s o n o f stand a r d u l t r a s o n o g r a p h i c images to the n o v e l fetal extremit'/fat a n d lean b o d y mass estimations. T h e coefficients o f v a r i a t i o n for a b d o m i n a l area a n d h e a d a r e a were 3.4% a n d 2.6%, respectively. Coefficients of variation for lean b o d y estimates o f t h e t h i g h a n d a r m were 4.9% a n d 7.5%, respectively, a n d 12.1% a n d 10.8% for estimates o f
Material and methods
T o establish r e p r o d u c i b l e criteria for the m e a s u r e m e n t of fetal fat a n d lean b o d y mass, we e x a m i n e d 25 w o m e n b e t w e e n 34 a n d 40 weeks' g e s t a t i o n with ultras o n o g r a p h y within 5 days o f delivery. S u b c u t a n e o u s fetal fat was e x a m i n e d in t h e m i d u p p e r a r m a n d m i d t h i g h by use o f s t a n d a r d i z e d cross-sectional images. 6' 7 E x t r e m i t y lean b o d y area was e x a m i n e d in t h e same cross-sectional m i d l i m b images. Fat c o n t e n t ( r e p o r t e d as area) was calculated as t h e total cross-sectional l i m b area m i n u s t h e c e n t r a l lean area ( i n c l u d i n g b o n e a n d muscle). A minim u m o f two estimates were m a d e o f e a c h p a r a m e t e r at e a c h observation. T h e m e a n value o f e a c h set o f observations was u s e d as t h e best estimate o f t h e area. T h e s e m e a s u r e s were t h e n c o m p a r e d , by simple c o r r e l a t i o n , with b i r t h w e i g h t a n d n e o n a t a l i n d e x values o f b o d y c o m p o s i t i o n d e t e r m i n e d by a n t h r o p o m e t r i c a s s e s s m e n t within 24 h o u r s o f delivery, s B i r t h weights within this g r o u p r a n g e d f r o m 2870 to 4450 gin, n e o n a t a l p o n d e r a l i n d e x was b e t w e e n 2.31 a n d 3.48, a n d e s t i m a t e d b o d y fat was b e t w e e n 7.3% a n d 20.3%. To d e t e r m i n e the a c c r e t i o n o f fat a n d lean b o d y mass u n d e r n o r m a l fetal g r o w t h c o n d i t i o n s , we r e c r u i t e d 36 n o n s m o k i n g w o m e n with a n o r m a l p r e p r e g n a n c y b o d y mass index. This was d e f i n e d as a p r e g r a v i d b o d y mass i n d e x (Body mass i n d e x = W e i g h t / H e i g h t 2 ) , w h i c h was > 1 5 t h a n d < 8 5 t h p e r c e n t i l e s o n t h e basis o f m a t e r n a l age. 9 All w o m e n h a d n o r m a l glucose s c r e e n i n g results o n t h e basis o f e i t h e r 1-hour glucose results ( < 1 3 5 m g / d l ) o r n o r m a l 3 - h o u r glucose t o l e r a n c e testing o n t h e basis
30
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Fig. 3. Midthigh central lean body area plotted against gestational age (GA). This relationship was best described by following polynomial: Midthigh lean area 564.6 48.2(GA) + 1.83(GA2). Adjusted R 2 = 0.86.
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Fig. 4. Midarm central lean body area plotted against gestational age (GA). This relationship was best described by following polynomial: Midarm lean area = -16.8 - 1.7(GA) + 0.35(GA2). Adjusted R 2 - 0.86.
T a b l e L C o r r e l a t i o n o f u h r a s o n o g r a p h i c a n d n e o n a t a l estimates o f b o d y c o m p o s i t i o n
Femoral fat area Estimated neonatal fat mass Sum of skinfolds (triceps-subscapular) Ponderal index Humeral fat area Estimated neonatal fat mass Sum of skinfolds (triceps-subscapular) Ponderal index Femoral lean area Birth weight Estimated neonatal lean mass Humeral lean area Birth weight Estimated neonatal lean mass
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0.56 0.53
p < 0.01 p < 0.01
NS, Not significant.
t h i g h a n d a r m fat mass. M1 n e o n a t e s were b o r n b e t w e e n 37 a n d 42 weeks' gestation, a n d b i r t h w e i g h t d i s t r i b u t i o n was c o n s i s t e n t with local p o p u l a t i o n - b a s e d standards. ~4 Two n e o n a t e s were < 1 0 t h p e r c e n t i l e , 32 n e w b o r n s were b e t w e e n t h e 10th a n d 9 0 t h percentiles, a n d 2 n e w b o r n s were > 9 0 t h p e r c e n t i l e (X2y, n o t significant). Stepwise regression analysis e s t a b l i s h e d best-fit e q u a t i o n s by leastsquares r e g r e s s i o n (p < 0.05 a c c e p t e d for significance). I n all p o o l e d analyses residuals f r o m t h e fitted regression were tested for r a n d o m n e s s a n d n o r m a l i t y a n d f o u n d to b e c o n s i s t e n t with g e n e r a l o r d i n a r y regression m o d e l r e q u i r e m e n t s . Established e q u a t i o n s e x a m i n e d the relat i o n s h i p b e t w e e n gestational age a n d e a c h o f t h e p a r a m eters m e a s u r e d . I n d e p e n d e n t variables i n c l u d e d gestational age (weeks), g e s t a t i o n a l age squared, m a t e r n a l age (years), parity ( n u l l i p a r o u s = 0, p a r o u s = 1), m a t e r n a l w e i g h t gain in p r e g n a n c y (kilograms), fetal g e n d e r (girl = 0, boy = 1), a n d m a t e r n a l p r e p r e g n a n c y w e i g h t (kilograms). Data are e x p r e s s e d as m e a n _ SD. Statistical
analysis was p e r f o r m e d with t h e S A S / C O M A S p r o g r a m , with p < 0.05 a c c e p t e d for significance.
Results S t a n d a r d m o r p h o m e t r i c m e a s u r e m e n t s were o b t a i n e d o f t h e fetal f e m u r a n d t h e BPD a n d a b d o m i n a l circumf e r e n c e at e a c h observation. T h e p a t t e r n o f growth m a t c h e d previously d e s c r i b e d g r o w t h charts. '5 A scatterg r a m o f t h e estimates o f h e a d area a n d a b d o m i n a l area is s h o w n in Figs. 1 a n d 2 p l o t t e d against g e s t a t i o n a l age. T h e r e l a t i o n s h i p o f b o t h fetal h e a d area a n d a b d o m i n a l area with gestational age follows t h e same r e l a t i o n s h i p with gestational age e s t a b l i s h e d by the c o r r e s p o n d i n g s i n g l e - d i m e n s i o n b o d y site m e a s u r e m e n t (i.e., BPD a n d abdominal circumference). The relationship between h e a d a r e a a n d gestational age is best r e p r e s e n t e d by a d e c e l e r a t i n g s e c o n d - o r d e r p o l y n o m i a l e q u a t i o n across gestational age, w h e r e a s a b d o m i n a l a r e a d e m o n s t r a t e s a l i n e a r r e l a t i o n s h i p with g e s t a t i o n a l age. T h e s e are con-
Bernstein et al.
Volume 176, N u m b e r l, Part 1 Am J Obstet Gynecol
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Fig. 5. Midthigh fat area plotted against gestational age (GA). This relationship was best described by following polynomial: Midthigh fat area = 645.6 - 61.9(GA) + 1.76(GA2) + 7.4(Maternal age) -3.9(Maternal prepregnancy weight). Adjusted R 2 = 0.80. Dashed line, 95% confidence limits of distribution.
Fig. 6. Midarm fat area ploned against gestational age (GA). This relationship was best described by following polynomial: Midarm fat area = 382.9 38.9(GA) + 1.07(GA~) + 5.03(Maternal age) 2.2(Maternal prepregnancy weight). Adjusted R ~ = 0.81. Dashed line, 95% confidence limits of distribution.
sistent with the relationship of BPD and abdominal circumference to gestational age. The evaluation of the correlation of the ultras 9 graphic estimates of fetal body composition and neonatal estimates of fat and lean body mass are presented in Table I. Significant correlations are observed with both birth weight and estimates of neonatal lean and fat mass. The relationship between gestational age for each of the measured variables is illustrated in Figs. 3 to 6. Figs. 3 and 4 demonstrate an accelerating deposition of extremity lean body mass as gestation advances. There is a fivefold to sevenfold increase in the cross-sectional area of the extremity lean body mass between 19 and 40 weeks of gestation. No i n d e p e n d e n t variables other than gestational age contributed to the stepwise regression. Figs. 5 and 6 illustrate the relationship between extremity fat deposition and gestational age. There is approximately a 10-fold increase in the cross-sectional area of the extremity subcutaneous fat mass between 19 and 40 weeks' gestation. In contrast with the lean body mass, the fat mass in both the arm and the thigh was significantly and positively associated with maternal age.
restricted neonate a low ponderal index (Rohrer's index of corpulence) has a stronger association than birth weight percentile with several specific morbidities. Is These studies support the valuable role of fetal fat assessment in the determination of risk associated with growth abnormality. The overall goal of the identification of fetal growth abnormality is the determination of elevated risk for morbidity or mortality. Ideal characteristics of a growth standard useful for the determination of growth abnormality would include (1) precise measurement capability, (2) sensitivity to environmental influences, and (3) growth occurring at a high rate during the period when abnormalities appear. The majority of routine ultras 9 graphic parameters (BPD, head circumference, femur length, head length) are valuable in the assessment of gestational age due in part to their resistance to environmental influences. This same quality makes them less well suited for the identification of growth abnormalities. Abdominal circumference, which demonstrates a unique linear growth profile compared with the bony parameters (decelerating quadratic equation), is the most sensitive of the individual ultrasonographic variables in detecting growth abnormalities. These findings may be linked in that rapid third-trimester growth allows for greater sensitivity in detecting factors that affect growth. The underlying physiologic features responsible for the unique growth profile of the abdominal circumference may lie in the fact that, unique among standard anthropometric measures, the abdominal circumference includes both lean mass (liver) and fat mass (subcutaneous and visceral). With regard to the specific patterns of tissue accretion identified in this study, similar results have been previously summarized. Cross-sectional data compiled by Sparks ~9 from h u m a n carcass analysis suggests that the
Comment
The h u m a n body is classically compartmentalized into fat and lean body mass components; it is the fat content that most accurately reflects energy stores and substrate availability. The use of an index of fat as a predictor of morbidity has been widely used in neonates. Whitelaw 16 has demonstrated that in infants of diabetic mothers subcutaneous fat was more closely associated than birth weight with maternal glucose control. Bernstein and Catalan 917 have shown that increased neonatal fat, indep e n d e n t of birth weight, was associated with a significant increase in the risk of birth by cesarean section in infants of women with gestational diabetes. In the growth-
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d e p o s i t i o n o f fetal fat follows a p a t t e r n t h a t accelerates as b i r t h w e i g h t advances, with d e p o s i t i o n rates m a x i m a l in t h e t h i r d trimester. In contrast, lean b o d y mass at t h e whole b o d y level a p p e a r s to follow a c o n s i s t e n t l i n e a r d e p o s i t i o n w h e n p l o t t e d across b i r t h weight. T h e comb i n e d l o n g i t u d i n a l a n d cross-sectional data p r e s e n t e d h e r e s u p p o r t t h e p a t t e r n o f fat d e p o s i t i o n i d e n t i f i e d by Sparks. O f i n t e r e s t is t h a t t h e a c c r e t i o n o f lean b o d y mass of t h e e n t i r e b o d y a p p e a r s l i n e a r w h e n it is assessed with cross-sectional data. However, w h e n b r o k e n d o w n i n t o distinct subsets, u n i q u e growth profiles appear. T h e s e subsets d e m o n s t r a t e e i t h e r a c c e l e r a t i o n ( p e r i p h e r a l muscle area), a l i n e a r r e l a t i o n s h i p ( a b d o m i n a l area), o r d e c e l e r a t i o n ( h e a d area) with a d v a n c i n g gestation. T h e n e t result o f these w o u l d a p p e a r linear. T h e i n d e p e n d e n t c o n t r i b u t i o n o f m a t e r n a l age to t h e a c c r e t i o n o f fetal fat is o f interest. A n increase in m a t e r n a l insulin resistance has b e e n associated with a d v a n c i n g age. 2~ Additionally, insulin resistance in t h e m o t h e r a p p e a r s to b e a n i m p o r t a n t c o n t r i b u t o r to n e o n a t a l fat c o n t e n t , m A link b e t w e e n a d v a n c i n g m a t e r n a l age a n d i n c r e a s e d insulin resistance in p r e g n a n c y is suggested by t h e data establishing inc r e a s e d m a t e r n a l age as a risk factor for t h e d e v e l o p m e n t o f g e s t a t i o n a l diabetes. 22' 23 We have previously e x a m i n e d t h e utility o f u l t r a s o n o g r a p h y to m e a s u r e s u b c u t a n e o u s fetal fat in the extremities. T h e use o f a simple l i n e a r m e a s u r e m e n t o f fat thickness across t h e e x t r e m i t y was f o u n d to b e poorly r e p r o d u c i b l e , with a n i n t r a o b s e r v e r coefficient o f variation o f 28% .6 This a p p e a r e d to b e t h e result o f distortion in t h e p r o x i m a l e x t r e m i t i e s r e s u l t i n g f r o m e x t e r n a l compression. T h e m e a s u r e m e n t o f fat area in the p r o x i m a l e x t r e m i t i e s has p r o v e d to b e m o r e r e p r o d u c i b l e . T h e coefficients o f v a r i a t i o n for t h e u l t r a s o n o g r a p h i c estim a t e s o f s u b c u t a n e o u s fat area in this study c o m p a r e r e a s o n a b l y with p u b l i s h e d coefficients o f variation for the m e a s u r e m e n t o f skinfold thickness in n e o n a t e s . "4 T h e accuracy o f t h e s e m e a s u r e m e n t s in t h e e s t i m a t i o n o f fetal fat is s u p p o r t e d by t h e significant c o r r e l a t i o n s with a n t h r o p o m e t r i c e s t i m a t i o n o f n e w b o r n body composition. T h e r e a p p e a r s to b e a s t r o n g e r c o r r e l a t i o n b e t w e e n m e a s u r e m e n t s o f t h e fetal thigh, r a t h e r t h a n t h e fetal arm, with n e o n a t a l estimates o f w h o l e b o d y fat a n d lean b o d y mass. We speculate t h a t t h e ability to m e a s u r e fetal fat area a n d c o m p a r e individual m e a s u r e m e n t s with these n o r m a t i v e values will b e o f assistance in t h e identification o f fetal g r o w t h a b n o r m a l i t i e s . REFERENCES
1. Chang TC, Robson SC, Boys RJ, SpencerJAD. Prediction of the small for gestational age infant: which ultrasonic measurement is best? Obstet Gynecol 1992;80:1030-8. 2. Tamura RK, Sabbagha RE, Depp R, Dooley SL, Socol ML.
3. 4.
5. 6. 7. 8. 9. 10. 11.
12. 13. 14.
15.
16. 17. 18.
19. 20. 21. 22.
23. 24.
Diabetic macrosomia: accuracy of third trimester ultrasound. Obstet Gynecol 1986;67:828-32. Rosati P, Exacoustos C, Caruso A, Mancuso S. Ultrasound diagnosis of fetal macrosomia. Ultrasound Obstet Gynecol 1992;2:23-90. Skovron ML, Berkowitz GS, Lapinski RH, KimJM, Chitkara U. Evaluation of early third-trimester ultrasound screening for intrauterine growth retardation.J Ultrasound Med 1991; 10:153-9. Camlano PM, Tyzbir ED, Allen SR, McBean JH, McAuliffe TL. Evaluation of fetal growth by estimation of neonalal body composition. Obstet Gynecol 1992;79:46-50. Bernstein IM, Catalano PM. Ultrasonographic estimation of fetal body composition for children of diabetic mothers. Invest Radiol 1991;26:722-6. Winn HN, Holcomb WL. Fetal nonmuscular soft tissue: a prenatal assessment. J Ultrasound Med 1993;4:197-9. Dauncey MJ, Candy G, Gardner D. Assessment of total body fat fi'om skinfold thickness measurements. Arch Dis Child 1977;52:223-7. Must A, Dallal GE, Dietz WH. Reference data for obesity: 85th and 95th percentiles of body mass index (wt/ht 2) and triceps skinfold thickness. Am J Clin Nutr 1991;53:839-46. Carpenter MW, Coustan DR. Criteria tot screening tests for gestational diabetes. AxnJ Obstet Gynecol 1982;144:768-73. Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal biparietal parameter: a critical re-evaluation of the relation to menstrual age by means of real-time uhrasound. J Ultrasound Med 1982;1:97-104. Hadlock FP, Deter RL, Harrist RB, Park SK. Fetal abdominal circumference as a predictor of menstrual age. AJR Am J Radiol 1982;139:367-70. Warda AH, Deter RL, Rossavik IK, Carpenter RJ, Hadlock FP. Fetal femur length: a critical reevaluation of the relationship to menstrual age. Obstet Gynecol 1985;66:69-75. Bernstein IM, Mohs G, Rucquoi M, Badger G. The case for hybrid fetal growth curves: a population based estimation of normal fetal size across gestational age. J Matern Fet Med 1996;5:124-7. Deter RL. Evaluation of studies of normal growth. In: Deter RL, Harrist RB, BirnholzJC, Hadlock FP, editors. Quantitative obstetrical ultrasonography. New York: Wiley, 1986:65112. V~hitelaw A. Subcutaneous fat in newborns infants of diabetic mothers: an indication of quality of diabetic control. Lancet 1977;1:15-8. Bernstein IM, Catalano PM. Examination of factors contributing to the risk of cesarean section in women with gestational diabetes. Obstet Gynecol 1994;83:462-5. Walther FJ, Raemaekers LHJ. The ponderal index as a measure of the nutritional status at birth and its relation to some aspects of neonatal morbidity. J Perinat Med 1982;10: 42-7. SparksJW. Human intrauterine growth and nutrient accretion. Semin Perinatol 1984;8:7.t-93. Defronzo RA. Glucose intolerance and aging: evidence for tissue insensitivity to insulin. Diabetes 1979;28:1095-101. Catalano PM, Drago NM, Amini SB. Maternal carbohydrate metabolism and its relationship to fetal growth and body composition, k a n J Obstet Gynecol 1995;172:1464-70. Coustan DR, Nelson CM, Carpenter MW, Carr SR, Rotendo L, Widness JA. Maternal age and screening for gestational diabetes: a population based study. Obstet Gynecol 1989;73: 557-61. O'sullivan JB, Mahan CM, Charles D, Dandrow RV. Screening criteria for high-risk gestational diabetic patients. Am J Obstet Gynecol 1973;116:895-900. McGowan A, Jordan M, MacGregor J. Skintbld thickness in neonates. Biol Neonate 1975;25:66-84.
Burlington, Vermont, Birmingham, Alabama, and Cleveland, Ohio OBJECTIVE: Our purpose was to examine the pattern of growth of both fetal lean body mass incorporating bone, brain, and muscle and subcutaneous fat mass during the course of normal pregnancy. We hypothesized that there are detectable differences in the accretion of fat versus lean body mass. STUDY DESIGN: To establish our method we correlated standardized cross-sectional ultrasonographic images of the fetal extremities with anthropometric assessment of neonatal body composition in 25 subjects. Subsequently 36 nonsmoking women with normal prepregnancy body mass index, normal glucose screening results, and no medical or obstetric complications were recruited. We performed 135 ultrasonographic examinations between 19 and 40 weeks' gestation (mean 3.8 scans per fetus, range 2 to 6) at 4-week intervals. Lean body mass measures included biparietal diameter, head circumference, and femur length. Fetal subcutaneous fat and lean body mass were examined both in the mid upper arm and midthigh by standardized cross-sectional images. All neonates were born between 37 and 42 weeks' gestation and had normal birth weight distribution. Stepwise regression analysis established best-fit equations for fetal measurements obtained ultrasonographically. Independent variables included gestational age, maternal age, weight gain in pregnancy, parity, fetal gender, and maternal prepregnancy weight. RESULTS: Fetal bone growth was best described by a second-order quadratic equation demonstrating deceleration with advancing gestational age (/3 < 0.0001, R2 0.92 to 0.96). A quadratic equation that accelerates with advancing gestation best described lean body mass accretion in the extremities (p < 0 . 0 0 0 1 , R 2 = 0.85 to 0 . 8 6 ) . Fetal fat deposition in the extremities was characterized by an accelerating quadratic equation when plotted against gestational age with maternal age and prepregnancy weight contributing significantly (p < 0.0001, R 2 = 0.80 to 0.81). CONCLUSION: Consistent with our hypothesis, fetal fat and lean body mass demonstrate unique growth profiles. We speculate that, as a result of an accelerated rate of growth in late gestation, the measurement of fetal fat will provide a more sensitive and specific marker of abnormal fetal growth when compared with index values of lean body mass. (Am J Obstet Gynecol 1997;176:28-32.)
Key words: Differential growth, fetal tissues, pregnancy, fetal growth, ultrasonography
Fetal size is most commonly characterized by comparison of ultrasonographically estimated fetal anthropometric parameters (abdominal circumference, biparietal diameter [BPD], femur length with population-based growth charts that establish normal size for each parameter across gestation. The most sensitive of the individual From the Department of Obstetrics and Gynecology, University of Vermont College of Medicine, a the Department of Nutrition Sciences, University of Alabama-Birmingham, b and the Department of Reproductive Biology, Case Western Reserve University at Metrohealth Medical Center.c Supported by a Mead Johnson/American College of Obstetricians and Gynecologists Clinical Research Fellowship (I.M.B.), the University of Vermont Sims Obesity~Nutrition Research Center, and the University of Vermont Clinical Research Center National Institutes of Health grant no. GCRC MO1-RRI09. Receivedfor publication April 11, 1996; revisedJuly 18, 1996; accepted August 14, 1996. Reprints not available from the authors. Copyright 9 1997 by Mosby-Year Book, Inc. 0002-9378/97 $5.00 + 0 6/1/77316 28
fetal parameters for the detection of growth abnormalities is the abdominal circumference. 1-a Estimated fetal weight, which is widely used as an index of fetal size, is generally estimated through a combination of parameters, routinely including abdominal circumference. Estimated fetal weight demonstrates predictive value similar to that of abdominal circumference. 1' 2.4 In the adult fat content correlates most directly with energy stores, and the distinction between fat mass and lean body mass is often used in the nutritional assessment of the individual. In the newborn, fat, although constituting only 12% to 14% of birth weight, has been demonstrated to account for 46% of the variance in neonatal weight. 5 These findings suggest to us the potential usefulness of ultrasonographically generated estimates of fetal fat for the determination and evaluation of fetal growth abnormalities. We therefore sought (1) to develop a method that would allow us to assess fetal fat
Bernstein et al.
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Fig. 1. Head area plotted across gestational age (GA). This relationship was best described by following polynomial: Head area = -10,157.5 + 775.3(GA) - 7.7(GA2). Adjusted R 2 = 0.94.
Fig. 2. Abdominal area plotted against gestational age (GA). This relationship was best described by following polynomial: Abdominal area = -7250.1 + 408.2(GA) + 28.8(Maternal age). Adjusted R z = 0.87.
a c c r e t i o n in u t e r o a n d t h e n (2) to d e t e r m i n e the g r o w t h rates of various fetal tissues with a focus o n d i s t i n g u i s h i n g b e t w e e n t h e a c c r e t i o n of fat mass a n d fat-free mass. We h y p o t h e s i z e d t h a t t h e r e w o u l d b e u n i q u e g r o w t h profiles associated with the d e p o s i t i o n o f fetal fat mass relative to l e a n b o d y mass.
o f t h e criteria of C a r p e n t e r a n d Coustan. 1~ All w o m e n were free o f m e d i c a l or obstetric disorders k n o w n to affect fetal growth. I n f o r m e d written c o n s e n t was obt a i n e d in a c c o r d a n c e with t h e University o f V e r m o n t C o m m i t t e e o n H u m a n R e s e a r c h for b o t h s e g m e n t s o f the study. A n A c u s o n ( M o u n t a i n View, Calif.) XP3 u n i t with a 3.5 M H Z c u r v i l i n e a r t r a n s d u c e r was u s e d for u h r a s o n o g r a p h i c e x a m i n a t i o n s . We p e r f o r m e d 135 ultras o n o g r a p h i c e x a m i n a t i o n s b e t w e e n 19 a n d 40 weeks' gestation ( m e a n 3.8 scans p e r fetus, r a n g e 2 to 6) at &week intervals. L e a n b o d y mass m e a s u r e s i n c l u d e d BPD, h e a d circumference, a n d f e m u r length. All p a r a m eters were evaluated by s t a n d a r d i z e d t e c h n i q u e s . 11-13 A b d o m i n a l c i r c u m f e r e n c e a n d a b d o m i n a l area were m e a s u r e d at the a n a t o m i c p l a n e s t a n d a r d i z e d for t h e assessment of t h e a b d o m i n a l circumference. A r e a meas u r e m e n t s o f the fetal h e a d were o b t a i n e d at t h e level o f t h e BPD. L e a n b o d y area a n d fat area in t h e e x t r e m i t i e s were m e a s u r e d as previously o u t l i n e d . All area m e a s u r e m e n t s were automatically calculated by the software p r o g r a m of the A c u s o n XP-3 w h e n t h e p e r i m e t e r estim a t e s o f a m e a s u r e d o b j e c t are e n t e r e d . G e s t a t i o n a l age a s s i g n m e n t was b a s e d o n the n u m b e r o f c o m p l e t e d m e n s t r u a l weeks. In all cases this a g r e e d with a n ultras o n o g r a p h i c e s t i m a t i o n of fetal size o b t a i n e d b e f o r e 20 weeks' gestation. I n t r a o b s e r v e r reliability for area meas u r e m e n t s o f t h e m i d h u m e r u s a n d m i d f e m u r fat a n d lean mass ( i n c l u d i n g b o n e a n d muscle) a n d fetal h e a d a n d a b d o m i n a l area was d e t e r m i n e d in 10 subjects. T h e coefficients o f v a r i a t i o n were calculated o n t h e basis o f area m e a s u r e m e n t s to allow d i r e c t c o m p a r i s o n o f stand a r d u l t r a s o n o g r a p h i c images to the n o v e l fetal extremit'/fat a n d lean b o d y mass estimations. T h e coefficients o f v a r i a t i o n for a b d o m i n a l area a n d h e a d a r e a were 3.4% a n d 2.6%, respectively. Coefficients of variation for lean b o d y estimates o f t h e t h i g h a n d a r m were 4.9% a n d 7.5%, respectively, a n d 12.1% a n d 10.8% for estimates o f
Material and methods
T o establish r e p r o d u c i b l e criteria for the m e a s u r e m e n t of fetal fat a n d lean b o d y mass, we e x a m i n e d 25 w o m e n b e t w e e n 34 a n d 40 weeks' g e s t a t i o n with ultras o n o g r a p h y within 5 days o f delivery. S u b c u t a n e o u s fetal fat was e x a m i n e d in t h e m i d u p p e r a r m a n d m i d t h i g h by use o f s t a n d a r d i z e d cross-sectional images. 6' 7 E x t r e m i t y lean b o d y area was e x a m i n e d in t h e same cross-sectional m i d l i m b images. Fat c o n t e n t ( r e p o r t e d as area) was calculated as t h e total cross-sectional l i m b area m i n u s t h e c e n t r a l lean area ( i n c l u d i n g b o n e a n d muscle). A minim u m o f two estimates were m a d e o f e a c h p a r a m e t e r at e a c h observation. T h e m e a n value o f e a c h set o f observations was u s e d as t h e best estimate o f t h e area. T h e s e m e a s u r e s were t h e n c o m p a r e d , by simple c o r r e l a t i o n , with b i r t h w e i g h t a n d n e o n a t a l i n d e x values o f b o d y c o m p o s i t i o n d e t e r m i n e d by a n t h r o p o m e t r i c a s s e s s m e n t within 24 h o u r s o f delivery, s B i r t h weights within this g r o u p r a n g e d f r o m 2870 to 4450 gin, n e o n a t a l p o n d e r a l i n d e x was b e t w e e n 2.31 a n d 3.48, a n d e s t i m a t e d b o d y fat was b e t w e e n 7.3% a n d 20.3%. To d e t e r m i n e the a c c r e t i o n o f fat a n d lean b o d y mass u n d e r n o r m a l fetal g r o w t h c o n d i t i o n s , we r e c r u i t e d 36 n o n s m o k i n g w o m e n with a n o r m a l p r e p r e g n a n c y b o d y mass index. This was d e f i n e d as a p r e g r a v i d b o d y mass i n d e x (Body mass i n d e x = W e i g h t / H e i g h t 2 ) , w h i c h was > 1 5 t h a n d < 8 5 t h p e r c e n t i l e s o n t h e basis o f m a t e r n a l age. 9 All w o m e n h a d n o r m a l glucose s c r e e n i n g results o n t h e basis o f e i t h e r 1-hour glucose results ( < 1 3 5 m g / d l ) o r n o r m a l 3 - h o u r glucose t o l e r a n c e testing o n t h e basis
30
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Fig. 3. Midthigh central lean body area plotted against gestational age (GA). This relationship was best described by following polynomial: Midthigh lean area 564.6 48.2(GA) + 1.83(GA2). Adjusted R 2 = 0.86.
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Fig. 4. Midarm central lean body area plotted against gestational age (GA). This relationship was best described by following polynomial: Midarm lean area = -16.8 - 1.7(GA) + 0.35(GA2). Adjusted R 2 - 0.86.
T a b l e L C o r r e l a t i o n o f u h r a s o n o g r a p h i c a n d n e o n a t a l estimates o f b o d y c o m p o s i t i o n
Femoral fat area Estimated neonatal fat mass Sum of skinfolds (triceps-subscapular) Ponderal index Humeral fat area Estimated neonatal fat mass Sum of skinfolds (triceps-subscapular) Ponderal index Femoral lean area Birth weight Estimated neonatal lean mass Humeral lean area Birth weight Estimated neonatal lean mass
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t h i g h a n d a r m fat mass. M1 n e o n a t e s were b o r n b e t w e e n 37 a n d 42 weeks' gestation, a n d b i r t h w e i g h t d i s t r i b u t i o n was c o n s i s t e n t with local p o p u l a t i o n - b a s e d standards. ~4 Two n e o n a t e s were < 1 0 t h p e r c e n t i l e , 32 n e w b o r n s were b e t w e e n t h e 10th a n d 9 0 t h percentiles, a n d 2 n e w b o r n s were > 9 0 t h p e r c e n t i l e (X2y, n o t significant). Stepwise regression analysis e s t a b l i s h e d best-fit e q u a t i o n s by leastsquares r e g r e s s i o n (p < 0.05 a c c e p t e d for significance). I n all p o o l e d analyses residuals f r o m t h e fitted regression were tested for r a n d o m n e s s a n d n o r m a l i t y a n d f o u n d to b e c o n s i s t e n t with g e n e r a l o r d i n a r y regression m o d e l r e q u i r e m e n t s . Established e q u a t i o n s e x a m i n e d the relat i o n s h i p b e t w e e n gestational age a n d e a c h o f t h e p a r a m eters m e a s u r e d . I n d e p e n d e n t variables i n c l u d e d gestational age (weeks), g e s t a t i o n a l age squared, m a t e r n a l age (years), parity ( n u l l i p a r o u s = 0, p a r o u s = 1), m a t e r n a l w e i g h t gain in p r e g n a n c y (kilograms), fetal g e n d e r (girl = 0, boy = 1), a n d m a t e r n a l p r e p r e g n a n c y w e i g h t (kilograms). Data are e x p r e s s e d as m e a n _ SD. Statistical
analysis was p e r f o r m e d with t h e S A S / C O M A S p r o g r a m , with p < 0.05 a c c e p t e d for significance.
Results S t a n d a r d m o r p h o m e t r i c m e a s u r e m e n t s were o b t a i n e d o f t h e fetal f e m u r a n d t h e BPD a n d a b d o m i n a l circumf e r e n c e at e a c h observation. T h e p a t t e r n o f growth m a t c h e d previously d e s c r i b e d g r o w t h charts. '5 A scatterg r a m o f t h e estimates o f h e a d area a n d a b d o m i n a l area is s h o w n in Figs. 1 a n d 2 p l o t t e d against g e s t a t i o n a l age. T h e r e l a t i o n s h i p o f b o t h fetal h e a d area a n d a b d o m i n a l area with gestational age follows t h e same r e l a t i o n s h i p with gestational age e s t a b l i s h e d by the c o r r e s p o n d i n g s i n g l e - d i m e n s i o n b o d y site m e a s u r e m e n t (i.e., BPD a n d abdominal circumference). The relationship between h e a d a r e a a n d gestational age is best r e p r e s e n t e d by a d e c e l e r a t i n g s e c o n d - o r d e r p o l y n o m i a l e q u a t i o n across gestational age, w h e r e a s a b d o m i n a l a r e a d e m o n s t r a t e s a l i n e a r r e l a t i o n s h i p with g e s t a t i o n a l age. T h e s e are con-
Bernstein et al.
Volume 176, N u m b e r l, Part 1 Am J Obstet Gynecol
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Fig. 5. Midthigh fat area plotted against gestational age (GA). This relationship was best described by following polynomial: Midthigh fat area = 645.6 - 61.9(GA) + 1.76(GA2) + 7.4(Maternal age) -3.9(Maternal prepregnancy weight). Adjusted R 2 = 0.80. Dashed line, 95% confidence limits of distribution.
Fig. 6. Midarm fat area ploned against gestational age (GA). This relationship was best described by following polynomial: Midarm fat area = 382.9 38.9(GA) + 1.07(GA~) + 5.03(Maternal age) 2.2(Maternal prepregnancy weight). Adjusted R ~ = 0.81. Dashed line, 95% confidence limits of distribution.
sistent with the relationship of BPD and abdominal circumference to gestational age. The evaluation of the correlation of the ultras 9 graphic estimates of fetal body composition and neonatal estimates of fat and lean body mass are presented in Table I. Significant correlations are observed with both birth weight and estimates of neonatal lean and fat mass. The relationship between gestational age for each of the measured variables is illustrated in Figs. 3 to 6. Figs. 3 and 4 demonstrate an accelerating deposition of extremity lean body mass as gestation advances. There is a fivefold to sevenfold increase in the cross-sectional area of the extremity lean body mass between 19 and 40 weeks of gestation. No i n d e p e n d e n t variables other than gestational age contributed to the stepwise regression. Figs. 5 and 6 illustrate the relationship between extremity fat deposition and gestational age. There is approximately a 10-fold increase in the cross-sectional area of the extremity subcutaneous fat mass between 19 and 40 weeks' gestation. In contrast with the lean body mass, the fat mass in both the arm and the thigh was significantly and positively associated with maternal age.
restricted neonate a low ponderal index (Rohrer's index of corpulence) has a stronger association than birth weight percentile with several specific morbidities. Is These studies support the valuable role of fetal fat assessment in the determination of risk associated with growth abnormality. The overall goal of the identification of fetal growth abnormality is the determination of elevated risk for morbidity or mortality. Ideal characteristics of a growth standard useful for the determination of growth abnormality would include (1) precise measurement capability, (2) sensitivity to environmental influences, and (3) growth occurring at a high rate during the period when abnormalities appear. The majority of routine ultras 9 graphic parameters (BPD, head circumference, femur length, head length) are valuable in the assessment of gestational age due in part to their resistance to environmental influences. This same quality makes them less well suited for the identification of growth abnormalities. Abdominal circumference, which demonstrates a unique linear growth profile compared with the bony parameters (decelerating quadratic equation), is the most sensitive of the individual ultrasonographic variables in detecting growth abnormalities. These findings may be linked in that rapid third-trimester growth allows for greater sensitivity in detecting factors that affect growth. The underlying physiologic features responsible for the unique growth profile of the abdominal circumference may lie in the fact that, unique among standard anthropometric measures, the abdominal circumference includes both lean mass (liver) and fat mass (subcutaneous and visceral). With regard to the specific patterns of tissue accretion identified in this study, similar results have been previously summarized. Cross-sectional data compiled by Sparks ~9 from h u m a n carcass analysis suggests that the
Comment
The h u m a n body is classically compartmentalized into fat and lean body mass components; it is the fat content that most accurately reflects energy stores and substrate availability. The use of an index of fat as a predictor of morbidity has been widely used in neonates. Whitelaw 16 has demonstrated that in infants of diabetic mothers subcutaneous fat was more closely associated than birth weight with maternal glucose control. Bernstein and Catalan 917 have shown that increased neonatal fat, indep e n d e n t of birth weight, was associated with a significant increase in the risk of birth by cesarean section in infants of women with gestational diabetes. In the growth-
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Bernstein et al.
January 1997 Am J Obstet Gynecol
d e p o s i t i o n o f fetal fat follows a p a t t e r n t h a t accelerates as b i r t h w e i g h t advances, with d e p o s i t i o n rates m a x i m a l in t h e t h i r d trimester. In contrast, lean b o d y mass at t h e whole b o d y level a p p e a r s to follow a c o n s i s t e n t l i n e a r d e p o s i t i o n w h e n p l o t t e d across b i r t h weight. T h e comb i n e d l o n g i t u d i n a l a n d cross-sectional data p r e s e n t e d h e r e s u p p o r t t h e p a t t e r n o f fat d e p o s i t i o n i d e n t i f i e d by Sparks. O f i n t e r e s t is t h a t t h e a c c r e t i o n o f lean b o d y mass of t h e e n t i r e b o d y a p p e a r s l i n e a r w h e n it is assessed with cross-sectional data. However, w h e n b r o k e n d o w n i n t o distinct subsets, u n i q u e growth profiles appear. T h e s e subsets d e m o n s t r a t e e i t h e r a c c e l e r a t i o n ( p e r i p h e r a l muscle area), a l i n e a r r e l a t i o n s h i p ( a b d o m i n a l area), o r d e c e l e r a t i o n ( h e a d area) with a d v a n c i n g gestation. T h e n e t result o f these w o u l d a p p e a r linear. T h e i n d e p e n d e n t c o n t r i b u t i o n o f m a t e r n a l age to t h e a c c r e t i o n o f fetal fat is o f interest. A n increase in m a t e r n a l insulin resistance has b e e n associated with a d v a n c i n g age. 2~ Additionally, insulin resistance in t h e m o t h e r a p p e a r s to b e a n i m p o r t a n t c o n t r i b u t o r to n e o n a t a l fat c o n t e n t , m A link b e t w e e n a d v a n c i n g m a t e r n a l age a n d i n c r e a s e d insulin resistance in p r e g n a n c y is suggested by t h e data establishing inc r e a s e d m a t e r n a l age as a risk factor for t h e d e v e l o p m e n t o f g e s t a t i o n a l diabetes. 22' 23 We have previously e x a m i n e d t h e utility o f u l t r a s o n o g r a p h y to m e a s u r e s u b c u t a n e o u s fetal fat in the extremities. T h e use o f a simple l i n e a r m e a s u r e m e n t o f fat thickness across t h e e x t r e m i t y was f o u n d to b e poorly r e p r o d u c i b l e , with a n i n t r a o b s e r v e r coefficient o f variation o f 28% .6 This a p p e a r e d to b e t h e result o f distortion in t h e p r o x i m a l e x t r e m i t i e s r e s u l t i n g f r o m e x t e r n a l compression. T h e m e a s u r e m e n t o f fat area in the p r o x i m a l e x t r e m i t i e s has p r o v e d to b e m o r e r e p r o d u c i b l e . T h e coefficients o f v a r i a t i o n for t h e u l t r a s o n o g r a p h i c estim a t e s o f s u b c u t a n e o u s fat area in this study c o m p a r e r e a s o n a b l y with p u b l i s h e d coefficients o f variation for the m e a s u r e m e n t o f skinfold thickness in n e o n a t e s . "4 T h e accuracy o f t h e s e m e a s u r e m e n t s in t h e e s t i m a t i o n o f fetal fat is s u p p o r t e d by t h e significant c o r r e l a t i o n s with a n t h r o p o m e t r i c e s t i m a t i o n o f n e w b o r n body composition. T h e r e a p p e a r s to b e a s t r o n g e r c o r r e l a t i o n b e t w e e n m e a s u r e m e n t s o f t h e fetal thigh, r a t h e r t h a n t h e fetal arm, with n e o n a t a l estimates o f w h o l e b o d y fat a n d lean b o d y mass. We speculate t h a t t h e ability to m e a s u r e fetal fat area a n d c o m p a r e individual m e a s u r e m e n t s with these n o r m a t i v e values will b e o f assistance in t h e identification o f fetal g r o w t h a b n o r m a l i t i e s . REFERENCES
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