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Prognostic significance of the human yolk sac assessed by ultrasonography
Prognostic significance of the human yolk sac assessed by ultrasonography E. Albert Reece, MD,8 Angela L. Scioscia, MD,8 Emese Pinter, MD," John C. Hobbins, MD,a Jacqueline Green, MS, RDMS,a Maurice J. Mahoney, MD,c and Frederick Naftolin, MD, DPhil• New Haven, Connecticut Ultrasonographic examinations were conducted between 6 and 12 weeks' gestation in 77 first-trimester pregnancies with normal fetal outcome . .Each examination consisted of measurements of the secondary yolk sac diameter and the fetal crown-rump length. The yolk sac was seen in all cases, and whereas its measurements demonstrated wide biologic variability, it correlated weakly (R2 = 0.39) with gesti;itional age as confirmed by crown-rump length measurements. Growth of the yolk sac diameter, although slight, assumed a curvilinear relationship with gestational age. Such a growth profile is best described by a second-degree polynomial regression equation. The yolk sac performs important functions for embryonic development during organogenesis and the remnant of the secondary yolk sac seen on ultrasonography is often considered to be a potential predictor of fetal outcome. Our findings indicate that the size of this remnant in pregnancies with normal karyotypes and normal fetal outcomes is extremely variable. Additionally, the yolk sac size in patients with karyotypic abnormalities and spontaneous abortion were equally variable and almost all were within the normal range. In light of these findings, the secondary yolk sac size does not appear to be a sensitive predictor of embryonic integrity and pregnancy outcome. (AM J 0BSTET GYNECOL
1988;159:1191-4.)
Key words: Yolk sac diameter, ultrasonography, crown-rump length
The human yolk sac contains no yolk material. However, it is the embryonic source of blood cells and blood vessels, primitive germ cells, and epithelia of the respiratory and digestive tracts, and it may account for the transfer of nutrients to the embryo at early stages in its development.' Since a portion of the early yolk sac becomes incorporated into the embryonic midgut and contributes to the aforementioned cells and tissues, we refer to the 12- to 25-day-old human yolk sac as the provisceral yolk sac instead of using the descriptive term secondary yolk sac, which is in common usage. We retain, however, the latter term for the extruded remnant of the provisceral yolk sac, which is found attached to the embryo after the fourth week of gestation (Fig. 1). 2 Ultrasonographic visualization of the secondary yolk sac was first described by Mantoni and Pedersen. 3 Since then, other investigators 4 • 5 have identified the secondary yolk sac between 6 and 12 weeks' gestation but have considered this organ to have little or no clinical sig-
nificance. Crooij et al. 5 reported a case in which the secondary yolk sac could not be visualized ultrasonographically, and the pregnancy ended in the spontaneous abortion of a fetus with a neural tube defect and no detectable yolk sac. We have also reported that during organogenesis, i.e., earlier than the abovementioned period, neural tube defects and other embryonic malformations were associated with yolk sac damage in rat conceptuses exposed to hyperglycemic culture conditions. 6 · 7 Furthermore, a recent clinical report" also suggested that this sonographically visible remnant may convey prognostic significance to a pregnancy. Therefore the purpose of this study was (1) to establish normative secondary yolk sac dimensions between 6 and 12 weeks' gestation and (2) to compare the secondary yolk sac diameter ih patients with aneuploidy or spontaneous abortions with the diameter in patients with euploidy and normal pregnancy outcome. The role of the yolk sac during organogenesis also is discussed.
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology," and the Departments of Pediatrics' and Human Genetics,' Yale University School of Medicine. Received for publication April 15, 1988; revised June 27, 1988; accepted July 7, 1988. Reprint requests: E. Albert.Reece, MD, Yale University School of Medicine, Department of Obstetrics and Gynecology, 333 Cedar St., P.O. Box 3333, New Haven, CT 06510.
Patients and methods The records of all patients undergoing chorionic villus sampling at the Yale-New Haven Hospital between 1983 and 1987 were scrutinized for possible entry into the study. Patients were included if yolk sac measurements were obtained at the time of the ultrasonographic examination. These patients underwent ultra-
1191
1192
Reece et al. Am
1\o\'ember 1988 Cynecol
J Obstet
Fig. 1. A, Ultrasonographic picture demonstrating the spherical secondan· rnlk sac (long arrow) with its central echolucencv; it is attached to the embryo by the yolk sac stalk. The umbilical cord is seen in cross section (short arrow). B, Schematic representation of an embryo at approximateh the same gestational age as that shown in A. The volk sac and umbilical cord are indicated.
sonographic examinations with either a General Electric RT 3000 (General Electric Corp., Rancho Cordova, Calif.) or a Technicare 280 SL (Johnson and Johnson, Independence, Ohio) sector scanner equipped with 5 MHz transducers. Each examination consisted of measurements of the secondarv volk sac diameters and the fetal crown-rump length. The crown-rump length was used to corroborate the gestational age. If a discrepancv of >5 days existed between the gestational age on the basis of menstrual date and the crown-rump length. the crown-rump length measurement was used to assign gestational age. Each pregnancv outcome was determined, and onlv those with normal karyotypes and outcomes were used in the initial computations to establish normal volk sac dimensions throughout pregnancv. During this same studv period, the yolk sac diameters of pregnancies with abnormal karyotypes or those that ended in spontaneous abortions were compared with those of the normal pregnancies. The collected data, which consisted of a single examination from each patient, were analyzed bv conducting scatter plots of volk sac diameter versus age with fitted regression lines. The growth curve assumed bv the volk sac was also described mathematicallv.
Results Seventv-seven pregnancies were examined between 6 and I 2 weeks' gestation. In all cases the volk sac was easilv visualized. The yolk sac was seen as a spherical structure often appearing in close proximitv to the embrvo and frequently seen attached bv its stalk to the embrvo (Fig. I). The yolk sac retained its spherical shape until the late first trimester, when an elongated
or Hattened appearance was occasionally observed. Under these circumstances the yolk sac diameter was computed bv a mean of the shortest and longest diameters. The fluid within the yolk sac was seen as an anechoic area; the vitelline vasculature on the surface of the volk sac could not be visualized. The volk sac diameters demonstrated wide biologic variability across gestational age, but there was a weak correlation (R" = 0.39) with gestational age. Fig. 2 depicts a scatter plot of the observed data with a fitted regression line of 95% confidence indicated. This figure also demonstrates that the normal secondary volk sac size increases slightly between 6 and 12 weeks' gestation. The growth profile appears to show a curvilinear relationship with gestational age, and the growth curve is best described by a second-degree polynomial regression equation.
Comment This study demonstrates that the secondary yolk sac can be consistently seen by sonography between 6 and I 2 weeks' gestation. However, bevond I 2 weeks the volk sac was rarely visualized. Embryonic growth, assessed bv measuring the long axis (crown-rump length) of the fetus, followed a linear growth pattern with gestational age as previously reported."· 10 The high-resolution ultrasound equipment used in our study had an axial resolution of I mm and could easily show a yolk sac diameter of ~3 mm in size. Textbooks of human embryology and reports from the Carnegie Laboratory of Embryology describe growth of the secondarv volk sac to be slow, with a size of about 5 mm in diameter achieved by 6 to 7 weeks' gesta-
Sonographic yolk sac assessment
Volume 159 Number 5
8
r2 = 0.39
y - 31.153308 • GA(-8.05972) •GA' 7~
7
*"~
6 Yolk Sac Diameter (mm)
5
0)4: /
~
*Oo *loo
"*
*
4
1193
0
3
.t. = aneuploidy
* = spontaneous abortion Gestational Age (weeks)
Fig. 2. Scatter plot with regression line of yolk sac diameters of euploid patients with normal sponpregnancy outcomes. The 95% confidence limits are indicated. Patients with aneuploidv and taneous abortions are indicated with arrowheads and asterisks, respecth·ely.
tion. 11.'" Crooij et al., 5 in an ultrasonog raphic study of 100 first-trimes ter pregnancie s, reported an increase in the secondary yolk sac diameter between 6 and 11 weeks' gestation, as well as an association with crownrump length. In their report, however, correlation coefficients were not reported, and the scatter of data points was wide. Therefore it is unclear what type of growth function was obtained. Although there is a slight increase in yolk sac growth between 6 and 12 weeks' gestation, the yolk sac diameter did not vary significantl y in abnormal conditions ~uch as aneuploidy or spontaneou s abortion. In fact, the structure we are imaging is only the extraembry onic remnant of the provisceral yolk sac, which by the fourth week has separated from the intraembry onic part already incorporat ed into the embryo to generate epithelia for the digestive and respiratory systems and to serve as a source of blood cells, blood vessels, and germ cells. The ultrasonogr aphically visible remnant seen attached to the embryo by the vitelline duct and the volk sac stalk is truly a "secondary yolk sac." It is unclear whether impaired growth and developme nt of the yolk sac associated with abnormal embryogen esis and pregnancy failure as described in animal studies done dur5 ing organogene sis6 · 7 or in the study by Crooij et al., conducted at a later stage, represent signs of yolk sac failure that precede embryonic maldevelop ment and/or pregnancy loss. Unfortunat ely, because of obvious limitations resulting from ethical and scientific reasons, there is a lack of human studies during the critical gestational period (days 12 to 25) when the human provisceral yolk sac makes its contributio n to organ formation. Studies such as the one described herein examine the
yolk sac at a time after the critical function is completed, so the lack of predictive value of this extraembry onic remnant with regard to embryonic integrity and outcome is not a surprise. The traditional notion is that the yolk sac is a vestigial organ without clinical significance in humans. We believe that this notion is an oversimplif ication. Experimen tal studies have demonstrated that the yolk sac is important to normal embryonic developme nt during organogene sis, and insults sustained by the yolk sac such as exposure to prolonged hyperglyce mia may result in anomalous developme nt of the conceptus. 6 · 7 Beyond this period, the role of the yolk sac is less well defined, and it may, in fact, be nonfunctio nal at this time. The primary yolk sac develops from the inner cell mass, opposite the amniotic cavity. As the amniotic cavity enlarges, it divides the yolk sac. The provisceral volk sac forms the ventral side of the embryo while the remainder of the primary yolk sac is extruded to lie on the surface of the placenta between the amniotic and 13 chorionic membranes . 11 · Before the provisceral volk sac becomes incorporat ed into the fetus to form part of the primitive gut, the endoderma l cells active Iv proliferate, even after the liver assumes its hematopoie tic function. These endoderma l yolk sac cells contain abundant rough endoplasm ic reticulum, glycogen, golgi bodies, and lysosomes and presumably have the 1 15 capacity for active biosyntheti c processes. '- In fact, it has been shown that the yolk sac is the source of several embryonic proteins including cx-fetoprotein, transferrin, prealbumin , albumin, cx 1-antitrypsin , and apolipoproteins.10· 16 11 Gonzales-C ruzzi and Roth studied the ultrastructural appearance of the hollow extraembry onic sec-
1194
Reece et al.
ondary yolk sac and described the mesothelial cells facing the exocoelom as possessing structural and functional specializations evidenced by a developed microvillous border, pinocytotic activity, the existence of a potential canalicular system at the cell interface, cytoplasmic protrusions, and a tendency to the formation of basal plasmolemmal infoldings. These features are characteristic of cells with intense absorptive activity. During this critical period of organogenesis, the hemochorial placenta is still imperfectly constituted, and the provisceral yolk sac is a prominent structure protruding into the exocoelomic cavity and having a complex cellular architecture and active biosynthetic and absorptive capacity. The authors commented that because the amnion does not come in contact with the chorion laeve until about the third month of gestation, during this time the transfer of nutrients to the fetus may occur via the yolk sac as an expansion or satellite of the fetal gut. These morphologic and functional capacities of the yolk sac during organogenesis (<8 weeks) would suggest a correlation between yolk sac morphology and embryonic-fetal development and pregnancy outcome. However, ultrasonographic studies such as ours done between 6 and 12 weeks' gestation examine the secondary yolk sac, which is nonfunctional and may have little or no prognostic significance for the embryonic integrity and outcome. In this study the size of the extruded portion of the secondary yolk sac was found to be an insensitive predictor of the embryonic status and its potential outcome. We thank Drs. Sandro Gabrielli and Mazen Abdalla for their assistance in the preparation of this manuscript. Statistical assistance by Ms. Theresa O'Connor, MPH, is also greatly appreciated. REFERENCES I. Moore KL. The developing human. Clinical oriented embryology. Philadelphia: WB Saunders, 1973:98.
!'l:ovember 1988 Am J Obstet Gynecol
2. Naftolin F, Diamond MP, Pinter E, Reece EA, Sanyal MK. A hypothesis concerning the general basis of organogenetic congenital anomalies. AM J 0BSTET GYNECOL 1987;157:1-4. 3. Mantoni M, Pedersen JF. Ultrasound visualization of the human yolk sac. JCU 1979;7:459. 4. Sauerbrei E, Cooperberg PL, Poland BJ. Ultrasound demonstration of the normal fetal yolk sac. JCU 1980;8:217. 5. Crooij MJ, Westhuis M, Shoemaker J, et al. Ultrasonographic measurement of the yolk sac. Br J Obstet Gynaecol 1982;89:93 l. 6. Reece EA, Pinter E, Leranth CZ, et al. Ultrastructural analysis of malformations of the embryonic neural axis induced by in vitro hyperglycemic conditions. Teratology 1985;3:363-73. 7. Pinter E, Reece EA, Leranth CA, et al. Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in conceptuses under hyperglycemic conditions. Teratology l 986;33:73-84. 8. Hurwitz SR. Yolk sac sign: sonographic appearance of the fetal yolk sac in missed abortion. J Ultrasound Med l 986;5:435-8. 9. Reece EA, Scioscia AL, Green J, O'Connor TZ, Hobbins JC. Embryonic trunk circumference: a new biometric parameter for estimation of gestational age. AM J 0BSTET GYNECOL 1987;156:713. 10. Robinson HP. The diagnosis of early pregnancy failure by sonar. Br J Obstet Gynaecol l 975;82:702. 11. Arey LB. In: Developmental anatomy. 7th ed. Philadelphia: WB Saunders, 1965:108. 12. O'Rahilly R. Developmental stages in human embryos. Washington DC: Carnegie Institute, 1973:65-8. 13. Lyons EA, Levi CS. Ultrasound in the first trimester of pregnancy. Radio! Clin North Am 1982;20:259. 14. Gonzales-Cruzzi F, Roth LM. The human yolk sac and yolk sac carcinoma: an ultrastructural study. Human Pathol 1976;7:675. 15. Hesseldahl H, Larson JF. Ultrastructure of the human yolk sac: endoderm, mesenchyme, tubules and mesothelium. AmJ Anat 1968;126:315. 16. Gitlin D, Perricelli A. Synthesis of serum albumin, pre-albumin, alpha-fetoprotein, alpha-1-antitrypsin and transferrin by the human yolk sac. Nature 1970;228: 995-7.
1988;159:1191-4.)
Key words: Yolk sac diameter, ultrasonography, crown-rump length
The human yolk sac contains no yolk material. However, it is the embryonic source of blood cells and blood vessels, primitive germ cells, and epithelia of the respiratory and digestive tracts, and it may account for the transfer of nutrients to the embryo at early stages in its development.' Since a portion of the early yolk sac becomes incorporated into the embryonic midgut and contributes to the aforementioned cells and tissues, we refer to the 12- to 25-day-old human yolk sac as the provisceral yolk sac instead of using the descriptive term secondary yolk sac, which is in common usage. We retain, however, the latter term for the extruded remnant of the provisceral yolk sac, which is found attached to the embryo after the fourth week of gestation (Fig. 1). 2 Ultrasonographic visualization of the secondary yolk sac was first described by Mantoni and Pedersen. 3 Since then, other investigators 4 • 5 have identified the secondary yolk sac between 6 and 12 weeks' gestation but have considered this organ to have little or no clinical sig-
nificance. Crooij et al. 5 reported a case in which the secondary yolk sac could not be visualized ultrasonographically, and the pregnancy ended in the spontaneous abortion of a fetus with a neural tube defect and no detectable yolk sac. We have also reported that during organogenesis, i.e., earlier than the abovementioned period, neural tube defects and other embryonic malformations were associated with yolk sac damage in rat conceptuses exposed to hyperglycemic culture conditions. 6 · 7 Furthermore, a recent clinical report" also suggested that this sonographically visible remnant may convey prognostic significance to a pregnancy. Therefore the purpose of this study was (1) to establish normative secondary yolk sac dimensions between 6 and 12 weeks' gestation and (2) to compare the secondary yolk sac diameter ih patients with aneuploidy or spontaneous abortions with the diameter in patients with euploidy and normal pregnancy outcome. The role of the yolk sac during organogenesis also is discussed.
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology," and the Departments of Pediatrics' and Human Genetics,' Yale University School of Medicine. Received for publication April 15, 1988; revised June 27, 1988; accepted July 7, 1988. Reprint requests: E. Albert.Reece, MD, Yale University School of Medicine, Department of Obstetrics and Gynecology, 333 Cedar St., P.O. Box 3333, New Haven, CT 06510.
Patients and methods The records of all patients undergoing chorionic villus sampling at the Yale-New Haven Hospital between 1983 and 1987 were scrutinized for possible entry into the study. Patients were included if yolk sac measurements were obtained at the time of the ultrasonographic examination. These patients underwent ultra-
1191
1192
Reece et al. Am
1\o\'ember 1988 Cynecol
J Obstet
Fig. 1. A, Ultrasonographic picture demonstrating the spherical secondan· rnlk sac (long arrow) with its central echolucencv; it is attached to the embryo by the yolk sac stalk. The umbilical cord is seen in cross section (short arrow). B, Schematic representation of an embryo at approximateh the same gestational age as that shown in A. The volk sac and umbilical cord are indicated.
sonographic examinations with either a General Electric RT 3000 (General Electric Corp., Rancho Cordova, Calif.) or a Technicare 280 SL (Johnson and Johnson, Independence, Ohio) sector scanner equipped with 5 MHz transducers. Each examination consisted of measurements of the secondarv volk sac diameters and the fetal crown-rump length. The crown-rump length was used to corroborate the gestational age. If a discrepancv of >5 days existed between the gestational age on the basis of menstrual date and the crown-rump length. the crown-rump length measurement was used to assign gestational age. Each pregnancv outcome was determined, and onlv those with normal karyotypes and outcomes were used in the initial computations to establish normal volk sac dimensions throughout pregnancv. During this same studv period, the yolk sac diameters of pregnancies with abnormal karyotypes or those that ended in spontaneous abortions were compared with those of the normal pregnancies. The collected data, which consisted of a single examination from each patient, were analyzed bv conducting scatter plots of volk sac diameter versus age with fitted regression lines. The growth curve assumed bv the volk sac was also described mathematicallv.
Results Seventv-seven pregnancies were examined between 6 and I 2 weeks' gestation. In all cases the volk sac was easilv visualized. The yolk sac was seen as a spherical structure often appearing in close proximitv to the embrvo and frequently seen attached bv its stalk to the embrvo (Fig. I). The yolk sac retained its spherical shape until the late first trimester, when an elongated
or Hattened appearance was occasionally observed. Under these circumstances the yolk sac diameter was computed bv a mean of the shortest and longest diameters. The fluid within the yolk sac was seen as an anechoic area; the vitelline vasculature on the surface of the volk sac could not be visualized. The volk sac diameters demonstrated wide biologic variability across gestational age, but there was a weak correlation (R" = 0.39) with gestational age. Fig. 2 depicts a scatter plot of the observed data with a fitted regression line of 95% confidence indicated. This figure also demonstrates that the normal secondary volk sac size increases slightly between 6 and 12 weeks' gestation. The growth profile appears to show a curvilinear relationship with gestational age, and the growth curve is best described by a second-degree polynomial regression equation.
Comment This study demonstrates that the secondary yolk sac can be consistently seen by sonography between 6 and I 2 weeks' gestation. However, bevond I 2 weeks the volk sac was rarely visualized. Embryonic growth, assessed bv measuring the long axis (crown-rump length) of the fetus, followed a linear growth pattern with gestational age as previously reported."· 10 The high-resolution ultrasound equipment used in our study had an axial resolution of I mm and could easily show a yolk sac diameter of ~3 mm in size. Textbooks of human embryology and reports from the Carnegie Laboratory of Embryology describe growth of the secondarv volk sac to be slow, with a size of about 5 mm in diameter achieved by 6 to 7 weeks' gesta-
Sonographic yolk sac assessment
Volume 159 Number 5
8
r2 = 0.39
y - 31.153308 • GA(-8.05972) •GA' 7~
7
*"~
6 Yolk Sac Diameter (mm)
5
0)4: /
~
*Oo *loo
"*
*
4
1193
0
3
.t. = aneuploidy
* = spontaneous abortion Gestational Age (weeks)
Fig. 2. Scatter plot with regression line of yolk sac diameters of euploid patients with normal sponpregnancy outcomes. The 95% confidence limits are indicated. Patients with aneuploidv and taneous abortions are indicated with arrowheads and asterisks, respecth·ely.
tion. 11.'" Crooij et al., 5 in an ultrasonog raphic study of 100 first-trimes ter pregnancie s, reported an increase in the secondary yolk sac diameter between 6 and 11 weeks' gestation, as well as an association with crownrump length. In their report, however, correlation coefficients were not reported, and the scatter of data points was wide. Therefore it is unclear what type of growth function was obtained. Although there is a slight increase in yolk sac growth between 6 and 12 weeks' gestation, the yolk sac diameter did not vary significantl y in abnormal conditions ~uch as aneuploidy or spontaneou s abortion. In fact, the structure we are imaging is only the extraembry onic remnant of the provisceral yolk sac, which by the fourth week has separated from the intraembry onic part already incorporat ed into the embryo to generate epithelia for the digestive and respiratory systems and to serve as a source of blood cells, blood vessels, and germ cells. The ultrasonogr aphically visible remnant seen attached to the embryo by the vitelline duct and the volk sac stalk is truly a "secondary yolk sac." It is unclear whether impaired growth and developme nt of the yolk sac associated with abnormal embryogen esis and pregnancy failure as described in animal studies done dur5 ing organogene sis6 · 7 or in the study by Crooij et al., conducted at a later stage, represent signs of yolk sac failure that precede embryonic maldevelop ment and/or pregnancy loss. Unfortunat ely, because of obvious limitations resulting from ethical and scientific reasons, there is a lack of human studies during the critical gestational period (days 12 to 25) when the human provisceral yolk sac makes its contributio n to organ formation. Studies such as the one described herein examine the
yolk sac at a time after the critical function is completed, so the lack of predictive value of this extraembry onic remnant with regard to embryonic integrity and outcome is not a surprise. The traditional notion is that the yolk sac is a vestigial organ without clinical significance in humans. We believe that this notion is an oversimplif ication. Experimen tal studies have demonstrated that the yolk sac is important to normal embryonic developme nt during organogene sis, and insults sustained by the yolk sac such as exposure to prolonged hyperglyce mia may result in anomalous developme nt of the conceptus. 6 · 7 Beyond this period, the role of the yolk sac is less well defined, and it may, in fact, be nonfunctio nal at this time. The primary yolk sac develops from the inner cell mass, opposite the amniotic cavity. As the amniotic cavity enlarges, it divides the yolk sac. The provisceral volk sac forms the ventral side of the embryo while the remainder of the primary yolk sac is extruded to lie on the surface of the placenta between the amniotic and 13 chorionic membranes . 11 · Before the provisceral volk sac becomes incorporat ed into the fetus to form part of the primitive gut, the endoderma l cells active Iv proliferate, even after the liver assumes its hematopoie tic function. These endoderma l yolk sac cells contain abundant rough endoplasm ic reticulum, glycogen, golgi bodies, and lysosomes and presumably have the 1 15 capacity for active biosyntheti c processes. '- In fact, it has been shown that the yolk sac is the source of several embryonic proteins including cx-fetoprotein, transferrin, prealbumin , albumin, cx 1-antitrypsin , and apolipoproteins.10· 16 11 Gonzales-C ruzzi and Roth studied the ultrastructural appearance of the hollow extraembry onic sec-
1194
Reece et al.
ondary yolk sac and described the mesothelial cells facing the exocoelom as possessing structural and functional specializations evidenced by a developed microvillous border, pinocytotic activity, the existence of a potential canalicular system at the cell interface, cytoplasmic protrusions, and a tendency to the formation of basal plasmolemmal infoldings. These features are characteristic of cells with intense absorptive activity. During this critical period of organogenesis, the hemochorial placenta is still imperfectly constituted, and the provisceral yolk sac is a prominent structure protruding into the exocoelomic cavity and having a complex cellular architecture and active biosynthetic and absorptive capacity. The authors commented that because the amnion does not come in contact with the chorion laeve until about the third month of gestation, during this time the transfer of nutrients to the fetus may occur via the yolk sac as an expansion or satellite of the fetal gut. These morphologic and functional capacities of the yolk sac during organogenesis (<8 weeks) would suggest a correlation between yolk sac morphology and embryonic-fetal development and pregnancy outcome. However, ultrasonographic studies such as ours done between 6 and 12 weeks' gestation examine the secondary yolk sac, which is nonfunctional and may have little or no prognostic significance for the embryonic integrity and outcome. In this study the size of the extruded portion of the secondary yolk sac was found to be an insensitive predictor of the embryonic status and its potential outcome. We thank Drs. Sandro Gabrielli and Mazen Abdalla for their assistance in the preparation of this manuscript. Statistical assistance by Ms. Theresa O'Connor, MPH, is also greatly appreciated. REFERENCES I. Moore KL. The developing human. Clinical oriented embryology. Philadelphia: WB Saunders, 1973:98.
!'l:ovember 1988 Am J Obstet Gynecol
2. Naftolin F, Diamond MP, Pinter E, Reece EA, Sanyal MK. A hypothesis concerning the general basis of organogenetic congenital anomalies. AM J 0BSTET GYNECOL 1987;157:1-4. 3. Mantoni M, Pedersen JF. Ultrasound visualization of the human yolk sac. JCU 1979;7:459. 4. Sauerbrei E, Cooperberg PL, Poland BJ. Ultrasound demonstration of the normal fetal yolk sac. JCU 1980;8:217. 5. Crooij MJ, Westhuis M, Shoemaker J, et al. Ultrasonographic measurement of the yolk sac. Br J Obstet Gynaecol 1982;89:93 l. 6. Reece EA, Pinter E, Leranth CZ, et al. Ultrastructural analysis of malformations of the embryonic neural axis induced by in vitro hyperglycemic conditions. Teratology 1985;3:363-73. 7. Pinter E, Reece EA, Leranth CA, et al. Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in conceptuses under hyperglycemic conditions. Teratology l 986;33:73-84. 8. Hurwitz SR. Yolk sac sign: sonographic appearance of the fetal yolk sac in missed abortion. J Ultrasound Med l 986;5:435-8. 9. Reece EA, Scioscia AL, Green J, O'Connor TZ, Hobbins JC. Embryonic trunk circumference: a new biometric parameter for estimation of gestational age. AM J 0BSTET GYNECOL 1987;156:713. 10. Robinson HP. The diagnosis of early pregnancy failure by sonar. Br J Obstet Gynaecol l 975;82:702. 11. Arey LB. In: Developmental anatomy. 7th ed. Philadelphia: WB Saunders, 1965:108. 12. O'Rahilly R. Developmental stages in human embryos. Washington DC: Carnegie Institute, 1973:65-8. 13. Lyons EA, Levi CS. Ultrasound in the first trimester of pregnancy. Radio! Clin North Am 1982;20:259. 14. Gonzales-Cruzzi F, Roth LM. The human yolk sac and yolk sac carcinoma: an ultrastructural study. Human Pathol 1976;7:675. 15. Hesseldahl H, Larson JF. Ultrastructure of the human yolk sac: endoderm, mesenchyme, tubules and mesothelium. AmJ Anat 1968;126:315. 16. Gitlin D, Perricelli A. Synthesis of serum albumin, pre-albumin, alpha-fetoprotein, alpha-1-antitrypsin and transferrin by the human yolk sac. Nature 1970;228: 995-7.