- Email: [email protected]
Second-trimester echogenic bowel and chromosomal abnormalities
Second-trimester echogenic bowel and chromosomal abnormalities Angela L. Scioscia, MD, Dolores H. Pretorius, MD, Nancy E. Budorick, MD, Timothy C. Cahill, MS, Fumiko T. Axelrod, MS, and George R. Leopold, MD San Diego and La Jalia, California OBJECTIVE: Our objective was to examine the outcomes of pregnancies in which echogenic bowel was detected in the second trimester. STUDY DESIGN: Twenty·two cases with a prospective diagnosis of echogenic bowel were reviewed. Karyotypic studies were performed in 19 cases, and 17 families had deoxyribonucleic acid-based risk assessment for cystic fibrosis. The echogenicity of the bowel was retrospectively reviewed and graded as mild or bright. RESULTS: Five cases of trisomy 21 and one case of trisomy 18 were detected; four of these had other ultrasonographic abnormalities. Twenty·seven percent of fetuses with echogenic bowel were aneuploid. Risk was greatest for cases with brightly echogenic bowel. No cystic fibrosis mutations were detected. The diagnosis of echogenic bowel was reproducible. CONCLUSION: Brightly echogenic bowel in the second trimester was found to be associated with a significant risk of fetal aneuploidy. (AM J OBSTET GVNECOL 1992;167:889-94.)
Key words: Echogenic bowel, chromosomal abnormalities, cystic fibrosis, fetal abnormalities, Down syndrome
Ultrasonographic detection of a hyperechoic mass in the fetal abdomen in the second trimester is an unusual occurrence. If acoustic shadowing and ascites are not present, this mass most likely represents the fetal bowel. The finding of echogenic bowel in the second trimester has been described by several authors as a normal variant. 1-:1 Other authors describe a similar image in fetuses with cystic fibrosis. l -b More recently, an association between chromosomal abnormalities and hyperechogenic bowel has been reported."" Nyberg et al." prospectively diagnosed echogenic bowel in 7% of second-trimester fetuses with Down syndrome. The recent identification of the gene responsible for cystic fibrosis and the precise characterization of a number of common mutations allow prenatal diagnosis of cystic fibrosis in situations where there is no family history or living proband available. Because of the association of echogenic bowel in the second trimester with cystic fibrosis and aneuploidy, in August 1990, we began offering families with this finding the options of prenatal diagnosis with amniocentesis and deoxyribonucleic acid (DNA)-based cystic fibrosis risk assess-
From the Departments of Reproductive Medicine, Radiology, and Medicine, University of California, San Diego. Presented at the Twelfth Annual Meeting of the Society of Perinatal Obstetriciam, Orlando, Florida, Februan 3-8, 1992. Reprint requests: Angela L. Scioscia, MD, Department of Reproductive Medicine, UCSD Medical Center-8433, 225 Dickinson St., Sail Diego, CA 92103. 6/6139691
ment. The purpose of this study was to determine the significance of echogenic bowel identified in the fetus during the second trimester.
Material and methods A review of cases with the prospective ultrasonographic diagnosis of echogenic bowel in the second trimester was undertaken. All studies were performed at the University of California, San Diego, Center for Fetal Diagnosis and Treatment, during a I-year period, from Aug. 1, 1990, through July 31,1991. Cases were ascertained by reviewing the logbooks of the DNA Laboratory, Ultrasound Unit, and (-;enetics Service; 22 cases were Identified. During this year approximately 2300 second- and third-trimester examinations were conducted; the majority of these were referred for advanced maternal age and maternal serum a-fetoprotein (AFP) screening abnormalities. The 22 cases with echogenic bowel were referred for the following indications: advanced maternal age 8, elevated maternal serum AFP 6, low maternal serum AFP 4, anatomic survey 2, and 2 with outside sonograms suggestive of echogenic bowel. Ultrasonographic examinations were performed with the Acuson XP and Acuson 128 equipment. A variety of transducers was utilized, including 3.5 and 5 MHz sector and linear-array transducers. All examinations were performed transabdominally. The fetal abdomen was imaged in both longitudinal and transverse planes. Echogenic bowel was diagnosed whenever
889
890
Sciascia et al.
October 1992 Am J Obstet Gynecol
Fig. 1. Longitudinal scan of normal I8-week fetus without echogenic bowel. (Head is to right.)
the attending physician thought the bowel was more echogenic than normal; it frequently approached the echogenicity of bone. Cases with intrinsic bowel abnormality, ascites, or acoustic shadowing were excluded. A normal fetus is seen in Fig. 1; Figs. 2 to 4 are images of three different fetuses with trisomy 21 and echogenic bowel. When echogenic bowel was seen in the second trimester, families were informed of the possible increased risk of cystic fibrosis and chromosomal abnormalities. The options of amniocentesis and DNA-based cystic fibrosis risk assessment were discussed and offered. Nineteen families chose amniocentesis whereas 17 pursued cystic fibrosis screening. High-molecular-weight genomic DNA was extracted from peripheral blood leukocytes and from cells cultured from the amniotic fluid with an automated nucleic acid extractor (Applied Biosystems 340A). DNA samples were screened for approximately 75% of cystic fibrosis mutations found in the white population. The delta F508, G551D, and R553X mutations were analyzed by polymerase chain reaction amplification." We have subsequently added the G542X, R560T, W1282X, and N1303K mutations to our screen. The primers and methods used for detection have been previously published.'O, 11 DNA haplotypes were determined by polymerase chain reaction with the use of restriction fragment length polymorphisms at the XV-2c and the KM19 loci.'2 In an effort to determine the reproducibility and
interobserver error of the diagnosis, the 22 cases with echogenic bowel and 10 randomly selected normal controls were reviewed by four sonologists (A.S., D.P., N.B., and G.L.). Reviewers were asked to grade the bowel pattern as normal, mildly echogenic, or bright. Bright cases were those in which the echogenicity approached that of the iliac wing; mild cases were intermediate between bright and normal. Five pregnancies were terminated by evacuation, and detailed gross and microscopic pathologic examination of the bowel was performed in three of these. Outcome data were obtained for all pregnancies. Results
The gestational age of the 22 cases with echogenic bowel was 18 :!: 2.4 weeks (mean:!: SD) with a range of 15 to 26 weeks. Karyotypic studies of the 19 pregnancies in which amniocentesis was performed revealed six trisomies. Five cases of Down syndrome (all trisomy 21) and one case of trisomy 18 were detected. During this time period 19 cases of Down syndrome and three cases of trisomy 18 were diagnosed in the second trimester at our center. The characteristics of the six chromosomally abnormal fetuses with midtrimester echogenic bowel and the ultrasonographic findings are described in Table I. Notably, in four of the trisomies other ultrasonographic abnormalities were detected; in two cases echogenic bowel was the only ultrasonographic abnormality. All trisomic cases with echogenic bowel were referred for indications that carried an in-
Volume 167 l'\umber 4, Part 1
Echogenic bowel and chromosomal abnormalities
891
Fig. 2. Longitudinal (A) and transverse (B) scans of 17 -week fetus with trisomy 21 and echogenic bowel (arrow), (A, Head to left; B, spine up.)
creased risk of aneuploidy. The three women who declined amniocentesis were delivered of phenotypically normal infants at term. The DNA studies for cystic fibrosis risk assessment failed to detect cystic fibrosis mutations in any of the fetuses or parents. The haplotype distribution of the non-Jewish white individuals approximated that re-
ported in ethnically similar normal populations. Cystic fibrosis was not diagnosed postnatally in any of the children, but they were < 1 year old at the time of follow-up. Pathologic examination of the fetal bowel, in two cases with trisomy 21 and one with trisomy 18, failed to detect any gross or microscopic abnormalities.
892
Scioscia et al.
October 1992 Am J Obstet Gynecol
Fig. 3. Longitudinal scan of 18-week fetus with trisomy 21 and echogenic bowel (arrow). (Head is to lefe)
Outcome data were obtained for all 22 cases. Termination of pregnancy was elected in five cases of fetal trisomy. One family elected to continue the pregnancy, and an infant with Down syndrome was born at term. Sixteen apparently normal pregnancies were continued. Thirteen infants were delivered at term without complications. There were three poor outcomes, all confined to the women with elevated maternal serum AFP levels: an intrauterine fetal death at 28 weeks, a previable premature delivery, and an infant with severe intrauterine growth retardation delivered at 32 weeks. Three of the five continued pregnancies with elevated maternal serum AFP had poor outcomes. The results of retrospective review of the 22 cases with echogenic bowel and 10 normal controls are as follows: In 15 cases all four sonologists agreed on the grade, in 14 cases three of four examiners agreed, and in three cases the assessment was discordant. In no instance did examiners disagree by more than one grade. A grade of mild or bright was assigned to each of the cases with a prospective diagnosis of echogenic bowel. Assignment was based on the consensus grade. Ten cases were classified as bright and 10 as mild. In two instances the grading was discordant; both of these fetuses had normal chromosome studies, and they were arbitrarily assigned to the bright category. This categorization resulted in 12 bright and 10 mild designations. Five of the trisomies were found in the bright
group, and one fetus with Down syndrome was found among the 10 mild cases. Comment
In this series of 22 cases of prospectively diagnosed echogenic bowel in the second trimester, six trisomic fetuses were detected. The risk of aneuploidy was 27%. The chromosomally abnormal pregnancies were already at increased risk, having been referred for advanced maternal age and abnormal maternal serum AFP levels. Four of the six aneuploid fetuses had other ultrasonographic abnormalities suggestive of a cl1fomosomal error. Two aneuploid fetuses had no other ultrasonographically detected abnormality. The risk of trisomy was much greater in those cases in which the bowel was retrospectively graded as bright (42%). In the 10 cases with mild increase in echogenicity, only one fetus with Down syndrome was detected. In 1988 Boue et al.,' reporting on the results of two large French multicenter collaborative studies of prenata'! diagnoses, noted an association of hyperechoic bowel and trisomy 21. Nyberg et al." presented the prenatal ultrasonographic findings in 94 cases of Down syndrome and found an association of echogenic bowel with Down syndrome. Of 68 cases of Down syndrome diagnosed in the second trimester, five were found to have echogenic bowel; one of these also had duodenal atresia.
Echogenic bowel and chromosomal abnormalities
VolUIlle 167 l'\lIIllber 4, Part 1
893
Fig. 4. Longitudinal scan of I H-week fetus with trisomy 21 and echogenic bowel (arrow), (Head is to left.)
Table I. Characteristics of pregnancies with echogenic bowel and aneuploidy Subject .\'0.
Gestatiollal age (71,10
illdiratioll
Kar)'otypl'
2 3 4
19 IH 17 IH
Advanced maternal age Advanced maternal age t :\laternal serum AFP t :\[aternal serum AFP
-l7,XY,+21 -l7,XY,+21 -l7,XX,+21 47,XX,+21
5
16
Advanced maternal age
-l7,XY,+21
6
19
i
-l7,XY,+ IH
:\[aternal serum AFP
A definitive pathologic explanation for the ultrasonographic finding was not found in the three cases examined at our institution. Reduced amniotic fluid microvillar enzymes have been demonstrated in fetuses with trisomy 21 and 18\J; this reduction is similar to that seen with cystic fibrosis, 111-, The abnormally low levels of microvillar enzvmes in fetuses with cystic fibrosis may be secondary effects of delayed passage of the tenacious meconium seen with this disorder. A similar mechanism may occur in the trisomic fetus. The delayed passage may be a result of decreased bowel motility or meconiulTl with abnormal characteristics.
Echogenic bowel only Echogenic bowel, nuchal area 5.7 n1ln Echogenic bowel only Echogenic bowel, bilateral choroid plexus cysts, nuchal area 4 mm, echogenic focus left ventricle Echogenic bowel, nuchal area 5.1 mm, echogenic focus left ventricle, short femur Echogenic bowel, bilateral choroid plexus cysts, ventriculoseptal defect, abnormal cerebellum, absellt kidIIC\', clubbed feet, clenched hands, ab~ent stomach
Cystic fibrosis mutations were not found in any of the parents or fetuses in this series, All the neonates are doing well to date; however, long-term follow-up is not yet available. Determination of the true risk of cystic fibrosis and the utility of DNA screening in this setting will require prospective evaluation of a larger number of patients. One cannot reliably diagnose cystic fibrosis by the findings of echogenic bowel and reduced microvillar intestinal enzymes without definitive DNA studies. There have been two reports of fetuses that, on prenatal evaluation, had echogenic bowel and reduced amniotic fluid microvillar enzymes; both of the
894 Sciascia et al.
neonates proved not to have cystic fibrosis on postnatal testing. 16• 17 If the ultrasonographic image of echogenic bowel is a result of delayed meconium passage, then a finding of reduced microvillar enzymes in the amniotic fluid might be expected, independent of cystic fibrosis. The diagnosis of echogenic bowel is qualitative; a number of factors can affect the image, including imaging at higher frequencies. In addition, bowel appears more echogenic with different equipment and settings. Our studies were performed on two very similar machines, so this was not a problem in our series. The consistency demonstrated in the retrospective review of the cases leads us to conclude that a diagnosis of echogenic bowel is reproducible and that interobserver variability is acceptable. In conclusion, brightly echogenic bowel in the second trimester is associated with a significant risk of chromosomal abnormality in a population at high risk for aneuploidy. The risk of cystic fibrosis with this ultrasonographic finding, in a population not at risk, has not been established. On the basis of this series and the experience reported in the literature, we recommend that women whose fetuses are found to have brightly echogenic bowel in the second trimester be offered amniocentesis. Until further data are collected, it would seem prudent also to offer DNA studies for cystic fibrosis. We acknowledge the efforts of the genetic counselors, ultrasonographers, and physicians of the University of California at San Diego Center for Fetal Diagnosis and Treatment. REFERENCES 1. Manco LG, Nunan FA, Sohnen H, jacobs EJ. Fetal small bowel simulating an abdominal mass at sonography. JCU 1986;14:404-7.
October 1992 Am J Obstet Gynecol
2. Fakhry j, Reiser M, Shapiro LR, Schechter A, Pait LP, Glennon A. Increased echogenicity in the lower fetal abdomen: a common normal variant in the second trimester. j Ultrasound Med 1986;5:489-92. 3. Parulekar SG. Sonography of normal fetal bowel. j Ultrasound Med 1991;10:210-1. 4. Muller F, Aubry MC, Gasser B, Duchatel F, Bouej, Boue A. Prenatal diagnosis of cystic fibrosis. II. Meconium ileus in affected fetuses. Pre nat Diagn 1985;5:109-17. 5. Meizner I. Letter to the editor. JCU 1987; 15:494. 6. Caspi B, Elchalal U, Lancet M, Chemke J. Prenatal diagnosis of cystic fibrosis: ultrasonographic appearance of meconium ileus in the fetus. Prenat Diagn 1988;8:37982. 7. Boue A, Muller F, Briard ML, Boue J. Interest of biology in the management of pregnancies where a fetal malformation has been detected by ultrasonography. Fetal Ther 1988;3:14-23. 8. Nyberg DA, Resta RG, Luthy DA, Hickok DE, Mahony BS, Hirsch jH. Prenatal sonographic findings of Down syndrome: review of 94 cases. Obstet Gynecol 1990;76:370-7. 9. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:487-91. 10. Kerem B, Zielenski j, Markiewicz D, et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Nat! Acad Sci USA 1990;87:8447-51. 11. Ng S, Pace R, Richard MV, et al. Methods for analysis of multiple cystic fibrosis mutations. Hum Genet 1991; 87:613-7. 12. Beaudet AL, Feldman GL, Fernbach SD, Buffone Gj, O'Brien WE. Linkage disequilibrium, cystic fibrosis, and genetic counseling. Am j Hum Genet 1989;44:319-26. 13. Brock DjH. Prenatal diagnosis of cystic fibrosis. In: Rodeck CH, Niclaides KH, eds. Prenatal diagnosis. Chichester: john Wiley, 1984: 159-70. 14. Mulivor RA, Cook D, Muller F, et al. Analysis of fetal intestinal enzymes in amniotic fluid for the prenatal diagnosis of cystic fibrosis. Am j Hum Genet 1987;40: 13146. 15. Gilbert F, Tsao K, Mendoza A, Mulivor R, Gluckson MM. Denning CR. Prenatal diagnostic options in cystic fibrosis. AMj OBSTET GYNECOL 1988;158:947-52. 16. Sharples PM, Hope PL, Wilkinson AR. False positive in prenatal diagnosis of cystic fibrosis. Lancet 1988; I :595. 17. Berry AC, Hogdson S. False positive in prenatal diagnosis of cystic fibrosis. Lancet 1988; I: 1333-4.
Key words: Echogenic bowel, chromosomal abnormalities, cystic fibrosis, fetal abnormalities, Down syndrome
Ultrasonographic detection of a hyperechoic mass in the fetal abdomen in the second trimester is an unusual occurrence. If acoustic shadowing and ascites are not present, this mass most likely represents the fetal bowel. The finding of echogenic bowel in the second trimester has been described by several authors as a normal variant. 1-:1 Other authors describe a similar image in fetuses with cystic fibrosis. l -b More recently, an association between chromosomal abnormalities and hyperechogenic bowel has been reported."" Nyberg et al." prospectively diagnosed echogenic bowel in 7% of second-trimester fetuses with Down syndrome. The recent identification of the gene responsible for cystic fibrosis and the precise characterization of a number of common mutations allow prenatal diagnosis of cystic fibrosis in situations where there is no family history or living proband available. Because of the association of echogenic bowel in the second trimester with cystic fibrosis and aneuploidy, in August 1990, we began offering families with this finding the options of prenatal diagnosis with amniocentesis and deoxyribonucleic acid (DNA)-based cystic fibrosis risk assess-
From the Departments of Reproductive Medicine, Radiology, and Medicine, University of California, San Diego. Presented at the Twelfth Annual Meeting of the Society of Perinatal Obstetriciam, Orlando, Florida, Februan 3-8, 1992. Reprint requests: Angela L. Scioscia, MD, Department of Reproductive Medicine, UCSD Medical Center-8433, 225 Dickinson St., Sail Diego, CA 92103. 6/6139691
ment. The purpose of this study was to determine the significance of echogenic bowel identified in the fetus during the second trimester.
Material and methods A review of cases with the prospective ultrasonographic diagnosis of echogenic bowel in the second trimester was undertaken. All studies were performed at the University of California, San Diego, Center for Fetal Diagnosis and Treatment, during a I-year period, from Aug. 1, 1990, through July 31,1991. Cases were ascertained by reviewing the logbooks of the DNA Laboratory, Ultrasound Unit, and (-;enetics Service; 22 cases were Identified. During this year approximately 2300 second- and third-trimester examinations were conducted; the majority of these were referred for advanced maternal age and maternal serum a-fetoprotein (AFP) screening abnormalities. The 22 cases with echogenic bowel were referred for the following indications: advanced maternal age 8, elevated maternal serum AFP 6, low maternal serum AFP 4, anatomic survey 2, and 2 with outside sonograms suggestive of echogenic bowel. Ultrasonographic examinations were performed with the Acuson XP and Acuson 128 equipment. A variety of transducers was utilized, including 3.5 and 5 MHz sector and linear-array transducers. All examinations were performed transabdominally. The fetal abdomen was imaged in both longitudinal and transverse planes. Echogenic bowel was diagnosed whenever
889
890
Sciascia et al.
October 1992 Am J Obstet Gynecol
Fig. 1. Longitudinal scan of normal I8-week fetus without echogenic bowel. (Head is to right.)
the attending physician thought the bowel was more echogenic than normal; it frequently approached the echogenicity of bone. Cases with intrinsic bowel abnormality, ascites, or acoustic shadowing were excluded. A normal fetus is seen in Fig. 1; Figs. 2 to 4 are images of three different fetuses with trisomy 21 and echogenic bowel. When echogenic bowel was seen in the second trimester, families were informed of the possible increased risk of cystic fibrosis and chromosomal abnormalities. The options of amniocentesis and DNA-based cystic fibrosis risk assessment were discussed and offered. Nineteen families chose amniocentesis whereas 17 pursued cystic fibrosis screening. High-molecular-weight genomic DNA was extracted from peripheral blood leukocytes and from cells cultured from the amniotic fluid with an automated nucleic acid extractor (Applied Biosystems 340A). DNA samples were screened for approximately 75% of cystic fibrosis mutations found in the white population. The delta F508, G551D, and R553X mutations were analyzed by polymerase chain reaction amplification." We have subsequently added the G542X, R560T, W1282X, and N1303K mutations to our screen. The primers and methods used for detection have been previously published.'O, 11 DNA haplotypes were determined by polymerase chain reaction with the use of restriction fragment length polymorphisms at the XV-2c and the KM19 loci.'2 In an effort to determine the reproducibility and
interobserver error of the diagnosis, the 22 cases with echogenic bowel and 10 randomly selected normal controls were reviewed by four sonologists (A.S., D.P., N.B., and G.L.). Reviewers were asked to grade the bowel pattern as normal, mildly echogenic, or bright. Bright cases were those in which the echogenicity approached that of the iliac wing; mild cases were intermediate between bright and normal. Five pregnancies were terminated by evacuation, and detailed gross and microscopic pathologic examination of the bowel was performed in three of these. Outcome data were obtained for all pregnancies. Results
The gestational age of the 22 cases with echogenic bowel was 18 :!: 2.4 weeks (mean:!: SD) with a range of 15 to 26 weeks. Karyotypic studies of the 19 pregnancies in which amniocentesis was performed revealed six trisomies. Five cases of Down syndrome (all trisomy 21) and one case of trisomy 18 were detected. During this time period 19 cases of Down syndrome and three cases of trisomy 18 were diagnosed in the second trimester at our center. The characteristics of the six chromosomally abnormal fetuses with midtrimester echogenic bowel and the ultrasonographic findings are described in Table I. Notably, in four of the trisomies other ultrasonographic abnormalities were detected; in two cases echogenic bowel was the only ultrasonographic abnormality. All trisomic cases with echogenic bowel were referred for indications that carried an in-
Volume 167 l'\umber 4, Part 1
Echogenic bowel and chromosomal abnormalities
891
Fig. 2. Longitudinal (A) and transverse (B) scans of 17 -week fetus with trisomy 21 and echogenic bowel (arrow), (A, Head to left; B, spine up.)
creased risk of aneuploidy. The three women who declined amniocentesis were delivered of phenotypically normal infants at term. The DNA studies for cystic fibrosis risk assessment failed to detect cystic fibrosis mutations in any of the fetuses or parents. The haplotype distribution of the non-Jewish white individuals approximated that re-
ported in ethnically similar normal populations. Cystic fibrosis was not diagnosed postnatally in any of the children, but they were < 1 year old at the time of follow-up. Pathologic examination of the fetal bowel, in two cases with trisomy 21 and one with trisomy 18, failed to detect any gross or microscopic abnormalities.
892
Scioscia et al.
October 1992 Am J Obstet Gynecol
Fig. 3. Longitudinal scan of 18-week fetus with trisomy 21 and echogenic bowel (arrow). (Head is to lefe)
Outcome data were obtained for all 22 cases. Termination of pregnancy was elected in five cases of fetal trisomy. One family elected to continue the pregnancy, and an infant with Down syndrome was born at term. Sixteen apparently normal pregnancies were continued. Thirteen infants were delivered at term without complications. There were three poor outcomes, all confined to the women with elevated maternal serum AFP levels: an intrauterine fetal death at 28 weeks, a previable premature delivery, and an infant with severe intrauterine growth retardation delivered at 32 weeks. Three of the five continued pregnancies with elevated maternal serum AFP had poor outcomes. The results of retrospective review of the 22 cases with echogenic bowel and 10 normal controls are as follows: In 15 cases all four sonologists agreed on the grade, in 14 cases three of four examiners agreed, and in three cases the assessment was discordant. In no instance did examiners disagree by more than one grade. A grade of mild or bright was assigned to each of the cases with a prospective diagnosis of echogenic bowel. Assignment was based on the consensus grade. Ten cases were classified as bright and 10 as mild. In two instances the grading was discordant; both of these fetuses had normal chromosome studies, and they were arbitrarily assigned to the bright category. This categorization resulted in 12 bright and 10 mild designations. Five of the trisomies were found in the bright
group, and one fetus with Down syndrome was found among the 10 mild cases. Comment
In this series of 22 cases of prospectively diagnosed echogenic bowel in the second trimester, six trisomic fetuses were detected. The risk of aneuploidy was 27%. The chromosomally abnormal pregnancies were already at increased risk, having been referred for advanced maternal age and abnormal maternal serum AFP levels. Four of the six aneuploid fetuses had other ultrasonographic abnormalities suggestive of a cl1fomosomal error. Two aneuploid fetuses had no other ultrasonographically detected abnormality. The risk of trisomy was much greater in those cases in which the bowel was retrospectively graded as bright (42%). In the 10 cases with mild increase in echogenicity, only one fetus with Down syndrome was detected. In 1988 Boue et al.,' reporting on the results of two large French multicenter collaborative studies of prenata'! diagnoses, noted an association of hyperechoic bowel and trisomy 21. Nyberg et al." presented the prenatal ultrasonographic findings in 94 cases of Down syndrome and found an association of echogenic bowel with Down syndrome. Of 68 cases of Down syndrome diagnosed in the second trimester, five were found to have echogenic bowel; one of these also had duodenal atresia.
Echogenic bowel and chromosomal abnormalities
VolUIlle 167 l'\lIIllber 4, Part 1
893
Fig. 4. Longitudinal scan of I H-week fetus with trisomy 21 and echogenic bowel (arrow), (Head is to left.)
Table I. Characteristics of pregnancies with echogenic bowel and aneuploidy Subject .\'0.
Gestatiollal age (71,10
illdiratioll
Kar)'otypl'
2 3 4
19 IH 17 IH
Advanced maternal age Advanced maternal age t :\laternal serum AFP t :\[aternal serum AFP
-l7,XY,+21 -l7,XY,+21 -l7,XX,+21 47,XX,+21
5
16
Advanced maternal age
-l7,XY,+21
6
19
i
-l7,XY,+ IH
:\[aternal serum AFP
A definitive pathologic explanation for the ultrasonographic finding was not found in the three cases examined at our institution. Reduced amniotic fluid microvillar enzymes have been demonstrated in fetuses with trisomy 21 and 18\J; this reduction is similar to that seen with cystic fibrosis, 111-, The abnormally low levels of microvillar enzvmes in fetuses with cystic fibrosis may be secondary effects of delayed passage of the tenacious meconium seen with this disorder. A similar mechanism may occur in the trisomic fetus. The delayed passage may be a result of decreased bowel motility or meconiulTl with abnormal characteristics.
Echogenic bowel only Echogenic bowel, nuchal area 5.7 n1ln Echogenic bowel only Echogenic bowel, bilateral choroid plexus cysts, nuchal area 4 mm, echogenic focus left ventricle Echogenic bowel, nuchal area 5.1 mm, echogenic focus left ventricle, short femur Echogenic bowel, bilateral choroid plexus cysts, ventriculoseptal defect, abnormal cerebellum, absellt kidIIC\', clubbed feet, clenched hands, ab~ent stomach
Cystic fibrosis mutations were not found in any of the parents or fetuses in this series, All the neonates are doing well to date; however, long-term follow-up is not yet available. Determination of the true risk of cystic fibrosis and the utility of DNA screening in this setting will require prospective evaluation of a larger number of patients. One cannot reliably diagnose cystic fibrosis by the findings of echogenic bowel and reduced microvillar intestinal enzymes without definitive DNA studies. There have been two reports of fetuses that, on prenatal evaluation, had echogenic bowel and reduced amniotic fluid microvillar enzymes; both of the
894 Sciascia et al.
neonates proved not to have cystic fibrosis on postnatal testing. 16• 17 If the ultrasonographic image of echogenic bowel is a result of delayed meconium passage, then a finding of reduced microvillar enzymes in the amniotic fluid might be expected, independent of cystic fibrosis. The diagnosis of echogenic bowel is qualitative; a number of factors can affect the image, including imaging at higher frequencies. In addition, bowel appears more echogenic with different equipment and settings. Our studies were performed on two very similar machines, so this was not a problem in our series. The consistency demonstrated in the retrospective review of the cases leads us to conclude that a diagnosis of echogenic bowel is reproducible and that interobserver variability is acceptable. In conclusion, brightly echogenic bowel in the second trimester is associated with a significant risk of chromosomal abnormality in a population at high risk for aneuploidy. The risk of cystic fibrosis with this ultrasonographic finding, in a population not at risk, has not been established. On the basis of this series and the experience reported in the literature, we recommend that women whose fetuses are found to have brightly echogenic bowel in the second trimester be offered amniocentesis. Until further data are collected, it would seem prudent also to offer DNA studies for cystic fibrosis. We acknowledge the efforts of the genetic counselors, ultrasonographers, and physicians of the University of California at San Diego Center for Fetal Diagnosis and Treatment. REFERENCES 1. Manco LG, Nunan FA, Sohnen H, jacobs EJ. Fetal small bowel simulating an abdominal mass at sonography. JCU 1986;14:404-7.
October 1992 Am J Obstet Gynecol
2. Fakhry j, Reiser M, Shapiro LR, Schechter A, Pait LP, Glennon A. Increased echogenicity in the lower fetal abdomen: a common normal variant in the second trimester. j Ultrasound Med 1986;5:489-92. 3. Parulekar SG. Sonography of normal fetal bowel. j Ultrasound Med 1991;10:210-1. 4. Muller F, Aubry MC, Gasser B, Duchatel F, Bouej, Boue A. Prenatal diagnosis of cystic fibrosis. II. Meconium ileus in affected fetuses. Pre nat Diagn 1985;5:109-17. 5. Meizner I. Letter to the editor. JCU 1987; 15:494. 6. Caspi B, Elchalal U, Lancet M, Chemke J. Prenatal diagnosis of cystic fibrosis: ultrasonographic appearance of meconium ileus in the fetus. Prenat Diagn 1988;8:37982. 7. Boue A, Muller F, Briard ML, Boue J. Interest of biology in the management of pregnancies where a fetal malformation has been detected by ultrasonography. Fetal Ther 1988;3:14-23. 8. Nyberg DA, Resta RG, Luthy DA, Hickok DE, Mahony BS, Hirsch jH. Prenatal sonographic findings of Down syndrome: review of 94 cases. Obstet Gynecol 1990;76:370-7. 9. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239:487-91. 10. Kerem B, Zielenski j, Markiewicz D, et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Nat! Acad Sci USA 1990;87:8447-51. 11. Ng S, Pace R, Richard MV, et al. Methods for analysis of multiple cystic fibrosis mutations. Hum Genet 1991; 87:613-7. 12. Beaudet AL, Feldman GL, Fernbach SD, Buffone Gj, O'Brien WE. Linkage disequilibrium, cystic fibrosis, and genetic counseling. Am j Hum Genet 1989;44:319-26. 13. Brock DjH. Prenatal diagnosis of cystic fibrosis. In: Rodeck CH, Niclaides KH, eds. Prenatal diagnosis. Chichester: john Wiley, 1984: 159-70. 14. Mulivor RA, Cook D, Muller F, et al. Analysis of fetal intestinal enzymes in amniotic fluid for the prenatal diagnosis of cystic fibrosis. Am j Hum Genet 1987;40: 13146. 15. Gilbert F, Tsao K, Mendoza A, Mulivor R, Gluckson MM. Denning CR. Prenatal diagnostic options in cystic fibrosis. AMj OBSTET GYNECOL 1988;158:947-52. 16. Sharples PM, Hope PL, Wilkinson AR. False positive in prenatal diagnosis of cystic fibrosis. Lancet 1988; I :595. 17. Berry AC, Hogdson S. False positive in prenatal diagnosis of cystic fibrosis. Lancet 1988; I: 1333-4.