Predicting the risk of cystic fibrosis with echogenic fetal bowel and one cystic fibrosis mutation

doi:10.1016/S0029-7844(99)00443-3

Obstetrics & Gynecology

Volume 94, Issue 6, December 1999, Pages 1020-1023

https://doi.org/10.1016/S0029-7844(99)00443-3 Get rights and content

Abstract

Objective: To assess fetal risk for cystic fibrosis when echogenic bowel and one cystic fibrosis mutation are detected.

Methods: A hypothetical cohort of 1000 women with singleton pregnancies and echogenic fetal bowel during the second trimester was used to determine the probability of cystic fibrosis when one cystic fibrosis transmembrane conductance regulator mutation was detected. The risk of cystic fibrosis was calculated using the range of prevalence of cystic fibrosis in fetuses with echogenic bowel reported in the literature. Risk calculations for fetuses of Ashkenazi Jewish, Northern European, African-American, Hispanic, and Asian descent accounted for carrier frequencies and mutation detection rates specific to each ethnic group.

Results: As the assumed prevalence of cystic fibrosis increases from 1–25%, the probability that a white fetus with one mutation and echogenic fetal bowel actually has cystic fibrosis increases from 4.8% to 62.5%. Assuming a 2% risk of cystic fibrosis with echogenic fetal bowel, an Ashkenazi Jewish fetus and an Asian fetus with echogenic bowel and one mutation have a 3.1% and 72% risk of cystic fibrosis, respectively. The probability of cystic fibrosis in a nonwhite fetus is between those two extremes.

Conclusion: The probability of cystic fibrosis after detection of echogenic bowel and one cystic fibrosis mutation varied among ethnic groups. Even at the highest prevalence of cystic fibrosis, most white fetuses will not have cystic fibrosis. In nonwhite populations almost half of these fetuses will have cystic fibrosis, even at the lowest prevalence of cystic fibrosis.

Section snippets

Materials and methods

We used a hypothetical cohort of 1000 singleton fetuses with second-trimester echogenic bowel to calculate the probability of cystic fibrosis when a single cystic fibrosis transmembrane conductance regulator mutation is detected (Figure 1). Cystic fibrosis detection rates for mutations in different ethnic populations were based on the National Institutes of Health’s Consensus Statement on Genetic Testing for Cystic Fibrosis.12

The reported prevalence of cystic fibrosis in fetuses with

Results

The model used to calculate the rate of cystic fibrosis among Northern European fetuses with echogenic bowel and one mutation is shown in Figure 1. In this population, approximately 4% (one in 25) are mutation carriers, with a mutation detection rate of 90%. Assuming a 2% prevalence of cystic fibrosis in fetuses with echogenic bowel, 20 of 1000 fetuses in our hypothetical cohort will have cystic fibrosis. With a 90% detection rate, 81% (16.2 of 20) of the fetuses with cystic fibrosis will have

Discussion

The genetic counseling that should be provided to women with fetuses having echogenic bowel and a single cystic fibrosis mutation has been debated. A prenatal diagnostic counseling dilemma arises when fetuses with echogenic bowel test positive for one cystic fibrosis mutation. The situation is difficult and not uncommon, especially in referral centers. Our analysis presents a theoretical model that permits calculation of the predicted rate of cystic fibrosis, given echogenic fetal bowel and a

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Cited by (22)

Isolated fetal echogenic bowel in a retrospective cohort: The role of infection screening
2018, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Once fetal echogenic bowel is diagnosed a flow-chart of additional investigations should be undertaken. Literature proposes investigation of history of uterine bleeding, Level-2 ultrasound (US) in a referral center for fetal medicine, counseling for eventual fetal karyotyping, parental and/or fetal screening for cystic fibrosis and TORCH infections serology [5,13–16]. While the role of fetal echogenic bowel as a soft marker for chromosomal abnormalities has been extensively investigated [5], the rate of fetal infection when this diagnosis occurs is less clear.
Fetal echogenic bowel (FEB) is an ultrasonographic marker of fetal infection. We aimed to determine the utility of infection screening when FEB is isolated.
Retrospective observational study of isolated FEB cases between 2006–2014. Infection screening included toxoplasmosis, rubella, syphilis, cytomegalovirus (CMV), herpes simplex virus and parvovirus B19. Fetal karyotyping, screening for cystic fibrosis (CF) and follow-up scans were also offered, according to international standards. Incidence of infection and 95% confidence interval (CI) were calculated.
148 patients with 154 fetuses were included. 4.7% of mothers developed acute infection: four patients developed CMV infection (2.7%, 95% CI 1.1–6.9%), in two fetuses infection was confirmed with amniocentesis and pregnancies were terminated; Parvovirus B19 infection was detected in 2 patients (1.4%, 95% CI 0.4–5.0) and confirmed in one fetus, which developed anemia; there was one toxoplasmosis maternal infection (0.7%, 95% CI 0.1–3.8%) treated with spyramicin, whose fetus was not infected. Percentage of chromosomal/genetic abnormalities was 3.2%, CF 1.3%, intra-amniotic bleeding 1.3%, FGR 34% and other ultrasonographic abnormalities at follow-up scans 18%.
The association between isolated FEB and fetal infection is uncommon (1.9% in our population). CMV maternal infection screening is supported by our findings, whereas screening for other infections needs to be further investigated.
Incidence and Carrier Frequency of CFTR Gene Mutations in Pregnancies With Echogenic Bowel in Nova Scotia and Prince Edward Island
2018, Journal of Obstetrics and Gynaecology Canada
Citation Excerpt :
Fetal echogenic bowel (echogenic bowel) is a sonographic marker associated with an increased incidence of fetal pathology, including cystic fibrosis, fetal aneuploidy, bowel pathology, and congenital infection, as well as placental insufficiency and fetal growth restriction.1–4
Fetal echogenic bowel (echogenic bowel) is associated with cystic fibrosis (CF), with a reported incidence ranging from 1% to 13%. Prenatal testing for CF in the setting of echogenic bowel can be done by screening parental or fetal samples for pathogenic CFTR variants. If only one pathogenic variant is identified, sequencing of the CFTR gene can be undertaken, to identify a second pathogenic variant not covered in the standard screening panel. Full gene sequencing, however, also introduces the potential to identify variants of uncertain significance (VUSs) that can create counselling challenges and cause parental anxiety. To provide accurate counselling for families in the study population, the incidence of CF associated with echogenic bowel and the carrier frequency of CFTR variants were investigated.
All pregnancies for which CF testing was undertaken for the indication of echogenic bowel (from Nova Scotia and Prince Edward Island) were identified (January 2007–July 2017). The CFTR screening and sequencing results were reviewed, and fetal outcomes related to CF were assessed.
A total of 463 pregnancies with echogenic bowel were tested. Four were confirmed to be affected with CF, giving an incidence of 0.9% in this cohort. The carrier frequency of CF among all parents in the cohort was 5.0% (1 in 20); however, when excluding parents of affected fetuses, the carrier frequency for the population was estimated at 4.1% (1 in 25). CFTR gene sequencing identified an additional VUS in two samples.
The incidence of CF in pregnancies with echogenic bowel in Nova Scotia and Prince Edward Island is 0.9%, with an estimated population carrier frequency of 4.1%. These results provide the basis for improved counselling to assess the risk of CF in the pregnancy, after parental carrier screening, using Bayesian probability. Counselling regarding VUSs should be undertaken before gene sequencing.
L'intestin échogène fœtal est associé à la fibrose kystique (FK), avec une incidence rapportée allant de 1 à 13 %. Le dépistage anténatal de la FK dans le contexte de l'intestin échogène peut se faire par l'analyse d'échantillons parentaux ou fœtaux visant à trouver des variants pathogènes du gène CFTR. Si un seul variant est détecté, le séquençage du gène CFTR peut être entrepris pour détecter un deuxième variant pathogène non couvert par les tests de dépistages standard. Le séquençage complet du gène risque toutefois de détecter des variants de signification incertaine (VSI) pouvant compliquer le counseling et causer de l'anxiété chez les parents. Afin de fournir des conseils avisés aux familles de la population à l'étude, nous nous sommes penchés sur l'incidence de la FK associée à l'intestin échogène et la fréquence de porteurs des variants du gène CFTR.
Nous avons relevé toutes les grossesses pour lesquelles un dépistage de la FK a été entrepris en raison d'un intestin échogène (en Nouvelle-Écosse et à l'Île-du-Prince-Édouard, de janvier 2007 à juillet 2017). Puis, nous avons examiné les résultats de dépistage et de séquençage du gène CFTR et évalué les issues fœtales liées à la FK.
Au total, 463 grossesses présentant un intestin échogène ont fait l'objet d'un dépistage. La présence de FK a été confirmée chez quatre fœtus, soit une incidence de 0,9 % dans cette cohorte. La fréquence de porteurs de FK parmi les parents de la cohorte était de 5,0 % (1 sur 20); cependant, lorsqu'on excluait les parents des fœtus atteints, la fréquence pour la population était estimée à 4,1 % (1 sur 25). Le séquençage du gène CFTR a permis de détecter un VSI supplémentaire dans deux échantillons.
L'incidence de la FK dans les grossesses présentant un intestin échogène en Nouvelle-Écosse et à l'Île-du-Prince-Édouard est de 0,9 %, et la fréquence de porteurs dans la population est estimée à 4,1 %. Ces résultats pourront servir à améliorer le counseling dans le but d'évaluer le risque de FK, après le dépistage des parents porteurs, à partir de la probabilité bayésienne. Un counseling concernant les VSI devrait être offert avant le séquençage.
Focus on cystic fibrosis and other disorders evidenced in fetuses with sonographic finding of echogenic bowel: 16-year report from Brittany, France
2010, American Journal of Obstetrics and Gynecology
Citation Excerpt :
We have already detailed the way to calculate such a risk in a previous article.20 This probability, relying on Bayesian calculations, heavily depends on the following 3 parameters: the prevalence of CF in fetuses with FEB, the carrier rate, and the mutation detection rate, which varies between geographic or ethnic groups and according to the molecular strategy chosen.5,30,31 Classically, the highest residual risk occurs in populations with the lowest detection rate and generally the lowest carrier frequency.
Pregnancies medical follow-up and ultrasonography development have enabled detection of fetal echogenic bowel, a sign associated with various pathologies, including cystic fibrosis. Based on the long experience of a region where cystic fibrosis is frequent (Brittany, France), we describe disorders diagnosed in fetal echogenic bowel fetuses and assess ultrasonography ability in detecting cystic fibrosis in utero.
We reviewed the cases of fetal echogenic bowel diagnosed in pregnant women living in Brittany and referred for CFTR gene analysis over the 1992-2007 period (n = 289).
A disorder was diagnosed in 32.2% of the fetuses, cystic fibrosis being the most commonly identified (7.6%). We also found digestive malformations (7.0%), chromosomal abnormalities (3.7%), and maternofetal infections (3.7%). Combining these data with our ongoing newborn screening program since 1989 showed that ultrasonography enabled diagnosis of 10.7% of the cystic fibrosis cases.
This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis.
Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders
2008, Genetics in Medicine
Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources.
Hyperechogenic fetal bowel: Counseling difficulties
2005, European Journal of Medical Genetics
Citation Excerpt :
Dense fetal bowel is found in 0.1–1.8% of second and third trimester pregnancies [6,13,3].
The detection of echodense fetal bowel on ultrasound examination in the second trimester of pregnancy justifies invasive procedures such as amniocentesis to detect an underlying cause. We present a case in which initial tests identified only one mutation in the cystic fibrosis transmembrane regulator (CFTR)-gene of the fetus, the family history being negative for CF. Strongly reduced intestinal enzyme activities suggested intestinal obstruction and further increased the estimated risk for CF. After the 24th gestational week, a second mutation was found, confirming cystic fibrosis in this child. Problems in counseling in this particular case are discussed.
Cystic fibrosis
2001, Clinics in Perinatology
Citation Excerpt :
Recent studies demonstrate that the risk of CF with prenatally detected echogenic bowel ranges from 1.3% to 13.3%.11,29,32 The ability to detect fetuses with CF by identifying echogenic bowel seems to be dependent on ethnic-racial background risks3,29; the detection of concurrent fetal anomalies (such detection lowers the risk for fetal CF)11; and ultrasound-specific issues, such as machine-technical issues and operator experience and variability.11 Fetal or parental assessment for CF should be offered when fetal echogenic bowel is detected in the second trimester, because even a 1.3% risk for an affected fetus is high enough to warrant further evaluation.29

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Original ArticlesPredicting the risk of cystic fibrosis with echogenic fetal bowel and one cystic fibrosis mutation

Abstract

Section snippets

Materials and methods

Results

Discussion

Lancet

Obstet Gynecol

Am J Obstet Gynecol

Sonographically detected hyperechoic fetal bowelSignificance and implications for pregnancy management

Obstet Gynecol

Is fetal hyperechoic bowel on second trimester sonogram an indication for amniocentesis?

Obstet Gynecol

Second trimester echogenic small bowelAn increased risk for adverse perinatal outcome

Prenat Diagn

Original Articles
Predicting the risk of cystic fibrosis with echogenic fetal bowel and one cystic fibrosis mutation