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Cystic Fibrosis and Chromosome Abnormalities Associated With Echogenic Fetal Bowel

From the Department of Pediatrics, New England Medical Center, Boston, Massachusetts; the Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, California; the Department of Biology, Brandeis University, Waltham, Massachusetts; and Genzyme Genetics, Framingham, Massachusetts.

Address reprint requests to: Beth M. Berlin, MS, New England Medical Center, Box 394, 750 Washington St., Boston, MA 02111, E-mail: beth.berlin{at}es.nemc.org

	Abstract

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Objective: To determine the prevalence of cystic fibrosis mutations and chromosome abnormalities in the fetuses of a heterogeneous population of pregnant women referred for prenatal testing for echogenic fetal bowel.

Methods: Fetal or parental samples obtained after a second-trimester sonographic finding of echogenic fetal bowel were submitted to a referral diagnostic laboratory during a 2-year period. Results of DNA testing and karyotyping on these samples were analyzed to determine the prevalence of cystic fibrosis transmembrane reductase gene mutations and chromosome abnormalities.

Results: Of 244 cases tested, two fetuses were positive for two cystic fibrosis mutations. This rate (0.8% or two of 244) is 20 times higher than the general white population rate of one per 2500. In a third case, both parents were carriers but the fetus was not tested. Nine (8%) of 113 fetuses tested had one cystic fibrosis mutation. Of 106 fetuses for whom chromosome results were available, three (2.8%) fetuses had a chromosomal abnormality: two had trisomy 21 and one had Klinefelter syndrome. A fourth fetus carried a de novo, apparently balanced, 5;12 translocation.

Conclusion: These laboratory results are representative of a broad spectrum of clinical settings and indicate a generalized increased risk associated with this sonographic finding. Therefore, when a second-trimester sonographic diagnosis of fetal echogenic bowel is made, fetal testing for both cystic fibrosis and chromosome abnormalities is warranted.

The clinical significance of the sonographic finding of echogenic fetal bowel has been the focus of increasing study. Although once most commonly described as a normal variant, the list of conditions for which echogenic bowel might be a sonographic marker has lengthened in recent years. It has now been reported in association with meconium ileus and cystic fibrosis, chromosomal abnormalities, cytomegalovirus infection, fetal growth restriction (FGR), and intestinal abnormalities such as atresia, stenosis, volvulus, and duplication.^1–3

Although many studies have been published, consensus regarding the magnitude of these risks and appropriate management guidelines for antenatally diagnosed echogenic fetal bowel do not yet exist. The rate of cystic fibrosis in the fetus with hyperechoic bowel has ranged from 0 to 52% in published studies.^4,5 Similarly, the percentage of fetuses with aneuploidy has ranged from 3.7% to 27%.^6,7 To further define the clinical significance of fetal echogenic bowel, we analyzed results of genetic testing of 244 cases ascertained in the second trimester from a variety of referral sites.

	Materials and Methods

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Two hundred forty-four cases of echogenic bowel were tested for cystic fibrosis, chromosome abnormalities, or both, during a 2-year period (May 1992 to April 1994) at Genzyme Genetics, Framingham, Massachusetts. Fetal bowel is considered hyperechoic if it has echogenicity similar to or greater than the surrounding bone. The diagnosis of echogenic bowel was made by the physician submitting the sample, and cases were referred by over 100 physicians.

Blood, cheek brush, or amniotic fluid samples were obtained at a number of referral centers. DNA testing for cystic fibrosis was done on the mother only (n = 16, 6.6%), both parents (n = 115, 47.1%), the fetus (n = 80, 32.8%), the mother and the fetus (n = 4, 1.6%), or both parents and the fetus (n = 29, 11.9%). Cases in which testing was done only on the mother often did not undergo further evaluation for cystic fibrosis if a mutation was not identified. Laboratory samples were accompanied by forms that indicated the reason for DNA testing, of which 84.8% indicated that an echogenic, hyperechoic, or bright bowel had been seen; and 15.2% indicated only abnormal findings on fetal ultrasound examination suggestive of cystic fibrosis. Because echogenic bowel, meconium peritonitis, and bowel obstruction are the only sonographic findings that have been associated with cystic fibrosis, we presumed that one of these findings was present in each of these other cases.

During the 2-year study period, testing became available for an increasing number of cystic fibrosis trans-membrane reductase mutations. Initially, individuals were tested for 12 mutations (n = 18, 7.4%), then 16 mutations (n = 106, 43.4%), and, as of late October 1993, 32 mutations (n = 117, 48.0%). The detection rate for cystic fibrosis carriers in the non-Jewish, white, northern European population was 83% for 12 mutations, 88% for 16 mutations, and 90% for 32 mutations. The detection rate for Ashkenazi Jewish cystic fibrosis carriers was 95% for 12 mutations and 97% for both 16 and 32 mutations. At 12, 16, and 32 mutations the cystic fibrosis carrier detection rate for black individuals was 45% (Genzyme Genetics Technical Advisory).

Results of fetal cytogenetic analysis were available for 106 cases (43.4%). Presumably, many of the other 138 subjects had cytogenetic evaluation done at the referring institution, and those results were not available for the present study.

In addition to results of cystic fibrosis and cytogenetic testing, maternal age, parental ethnicity, gestational age, type of sample received, and number of mutations for which the individuals were tested were recorded.

Statistical analysis was performed using Fisher exact test as calculated using Epi Info Version 6 calculation package (Division of Surveillance and Epidemiology, Centers for Disease Control, Atlanta, GA). Results are expressed as relative risk (RR) with 95% confidence intervals (CI).

	Results

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A total of 244 families were tested for cystic fibrosis because of a second-trimester sonographic diagnosis of fetal echogenic bowel. The ethnic background of patients tested for cystic fibrosis is shown in Table 1. The fetus was found to be a carrier of one cystic fibrosis mutation in nine of 113 cases in which fetal testing was done (8%). In five cases, one parent was found to carry a mutation and the other parent had no mutation identified; in these families the fetus was not tested. There were two (0.8%) fetuses predicted to have cystic fibrosis; one was homozygous for the F508 mutation and the other had one F508 mutation and one R117H mutation. This rate (0.8% or two per 244) is 20.4 times higher than the general white population rate of one per 2500 live births (CI 4.0 < RR < 105.5, P = .007). In a third case, both parents were carriers of cystic fibrosis mutations (N1303K and 711+1G–>T) but elected not to have amniocentesis for fetal testing (Table 2). If this third fetus were affected, the risk of cystic fibrosis in this prenatal population would be 1.2% or one per 81, which is 30.7 times higher than the general white population rate (CI 8.6 < RR < 111.1, P < .001).

Cytogenetic testing results were available for 106 fetuses, or 43.4% of the sample. Four fetuses, or 3.8% of those tested, had a chromosomal abnormality. Two of these fetuses had trisomy 21 (1.9%), one had Klinefelter syndrome (47,XXY), and one had an apparently balanced translocation involving chromosomes 5 and 12. One of the fetuses with trisomy 21 had choroid plexus cysts as well as an echogenic bowel. The mothers of the two fetuses with trisomy 21 were 34 and 43 years old. The echogenic bowel was noted at 16 weeks’ gestation in both cases.

The maternal age of patients ranged from 13 to 46 years, with a mean age of 29 years. The mean age of the women for whom cytogenetic results were available was 28.9 years. Fifty-three mothers (21.7%) were 35 years or older at the time of testing. The risk of chromosome abnormalities appears to be greater in this study population than would be expected in a population with a mean maternal age of 29 years (one per 416 at livebirth⁸).

	Discussion

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We examined the prevalence of cystic fibrosis and chromosome abnormalities among 244 cases referred to a large genetics laboratory because of a sonographic indication of fetal echogenic bowel. Although our results show a lower incidence of both outcomes than previous studies,^1,2,7 both conditions were higher than the expected background risk. The prevalence of confirmed cystic fibrosis in our study was 0.8%, or approximately one per 125, 20 times higher than the one per 2500 prevalence in the general white population. Given the high likelihood that the untested fetus with echogenic bowel and two carrier parents was also affected, the RR would then increase to 30 when compared with the general white population. Although these relative risks are quite high, the outcome (cystic fibrosis) is still rare in the population, and a much larger sample size would be necessary to confirm our results and the absolute risk for cystic fibrosis in this setting.

The prevalence of clinically significant chromosome abnormalities was 2.8% (one per 35 fetuses), and the prevalence of trisomy 21 specifically was 1.9% (one per 53 fetuses). This risk of chromosome abnormalities appears to be higher than the predicted risk in a population with a mean maternal age of 28.9 years, although without more information on these subjects (ie, biochemical screening results and other ultrasound information), the RR of a chromosome abnormality in this population could not be defined with certainty.

Of primary importance in determining the significance of echogenic bowel are the a priori risks of aneuploidy or cystic fibrosis. These risks are determined by maternal age, results of biochemical serum screening, presence of other fetal structural anomalies, family history, and ethnic background. In many studies of echogenic bowel, that information is incompletely ascertained or reported. Our study was also limited by incomplete access to that information. Although several DNA test request forms specified other problems in addition to the echogenic bowel (eg, elevated maternal serum alphafetoprotein, FGR, and oligohydramnios), it is unknown whether the fetuses for whom only echogenic bowel was indicated had other problems that were not reported.

Studies of echogenic fetal bowel are also limited by the subjective nature of this sonographic finding. Research aimed at quantification of echogenicity indicates that both cystic fibrosis and aneuploidy are more common as the degree of echogenicity increases.^9,10 Lack of standardization in the definition of clinically significant echogenic bowel will result in a higher number of false-positive diagnoses. Our study included a referral base of over 100 physicians, and no consistent definition of echogenic bowel was possible. However, these results are more reflective of the real world, where echogenic bowel will initially be diagnosed. A study in a single center with a limited number of sonographers will have findings less generalizable to the broad range of practitioners performing obstetric ultrasound examination. Our study has the advantage of determining a risk that is more applicable to the general obstetric population.

	Footnotes

 
Financial Disclosure
Authors Sugarman and Allitto are employees of Genzyme Genetics.

PII S0029-7844(99)00286-0

Received June 15, 1998. Received in revised form December 30, 1998. Accepted January 20, 1999.

	References

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4. Sepulveda W, Leung KY, Robertson ME, Kay E, Mayall ES, Fisk NM. Prevalence of cystic fibrosis mutations in pregnancies with fetal echogenic bowel. Obstet Gynecol 1996;87:103–6.[Abstract]

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6. Bahado-Singh R, Morotti R, Copel JA, Mahoney MJ. Hyperechoic fetal bowel: The perinatal consequences. Prenat Diagn 1994;14: 981–7.[Medline]

7. Scioscia AL, Pretorius DH, Budorick NE, Cahill TC, Axelrod FT, Leopold GR. Second-trimester echogenic bowel and chromosomal abnormalities. Am J Obstet Gynecol 1992;167:889–94.[Medline]

8. Hook EB. Rates of chromosomal abnormalities at different maternal ages. Obstet Gynecol 1981;58:282–5.[Abstract/Free Full Text]

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