Objective
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.
Study Design
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).
Results
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.
Conclusion
This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis.
Routine medical follow-up of pregnancies and development of ultrasonography have enabled the sonographic detection of fetal echogenic bowel (FEB), a sign that may be suggestive of various deleterious conditions. FEB, in which the echogenicity of the bowel is similar to or greater than that of the surrounding bone, is usually diagnosed during the second trimester of pregnancy. This sign has been associated with a large range of conditions, such as chromosomal abnormalities, congenital viral infections, digestive tract malformations, and cystic fibrosis (CF), but it may also be totally benign and disappear spontaneously.
In the case of CF, FEB may be an early sign of meconium ileus and therefore justifies a molecular analysis of the gene responsible for CF—the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene—in the couple or in the couple and the fetus.
CF (OMIM:219700) is one of the most common autosomal recessive disorders in white populations, with an incidence of about 1 of 3500 live births and a carrier rate of about 1 of 30. This disease is characterized by abnormal exocrine gland secretions and leads, in its classic form, to chronic pulmonary infections and pancreatic insufficiency. Although patients’ life expectancy has steadily improved over the past decades, CF remains a severe and incurable disease.
This disease is caused by mutations in the CFTR gene, which was cloned in 1989, and encodes a chloride channel whose malfunction leads to the dehydration and thickening of mucous secretions. To date, more than 1800 mutations have been identified in the CFTR gene worldwide, and the techniques available for detecting these mutations have greatly evolved since the discovery of the gene in 1989. The molecular analysis performed when FEB is diagnosed enables the identification of new 1-in-4 risk couples in families with no history of CF who then have the possibility of opting for prenatal diagnosis.
In our area (Brittany, western France), where CF is frequent (incidence: 1 of 2900), analysis of the CFTR gene after FEB diagnosis has been in place since the early 1990s, and the aim of this study is to report the long experience of Brittany in that field (period 1992-2007). More precisely, this article describes the type and frequency of the various disorders diagnosed in fetuses with FEB. It emphasizes the prevalence of CF and the carrier rate in that population and assesses the ability of ultrasonography to detect CF in utero.
Materials and Methods
Study population
Located at the western end of Europe, Brittany is a region of western France with 3 million inhabitants (mostly of Celtic origin) and an average of about 37,000 births every year. This area is one of the most affected by CF worldwide and has a long experience in newborn screening for CF (implemented since 1989), as well as in multidisciplinary management of CF patients. Consequently, practitioners are particularly aware of this disease and sensitive to all the clinical signs that could lead to a diagnosis of CF.
In this study, we reviewed each consecutive case of FEB diagnosed in pregnant women living in Brittany who were referred by gynecologists or sonographers for analysis of the CFTR gene over the period 1992-2007. These data were collected by the 2 genetic laboratories involved in the analysis of the CFTR gene in Brittany (University Hospitals of Brest and Rennes). Requests for CFTR gene analysis prompted by abnormal ultrasound scans, such as absence of a gallbladder, fetal ascites, and intraabdominal calcifications, were excluded from the study (which represented 57 cases over the study period).
The research protocol was approved by the Comité Consultatif sur le Traitement de l’Information en Matière de Recherche dans le domaine de la Santé and by the Commission Nationale d’Informatique et des Libertés.
Management of pregnancies with a diagnosis of FEB
In France, a routine medical monitoring of pregnancies is implemented, which includes 3 obligatory ultrasound examinations (1 per trimester, usually done at 10, 22, and 32 weeks of gestation). It is generally during the second trimester that FEB may be diagnosed.
In Brittany, health practitioners in charge of pregnancy monitoring (in particular gynecologists, obstetricians, and sonographers) have developed a specific organization, in which cases of FEB are usually referred to a reference sonographer specialist, which must confirm or refute the diagnosis of FEB.
Couples in whom FEB is detected during pregnancy are referred for genetic counseling to explain the possibility of prenatal examinations to investigate its cause, as well as the possibility of a pregnancy termination if a severe disease is diagnosed. Simultaneously, CFTR gene analysis, fetal karyotyping, and screening for infections, including cytomegalovirus and toxoplasmosis, are offered to the couples.
CFTR gene analysis
Techniques for identifying CFTR mutations have gradually improved since the discovery of the CFTR gene in 1989, with the most recent advances enabling detection of large genomic rearrangements and copy number variations by comparative genomic hybridization array. Nevertheless, it remains difficult to detect all the mutations of this gene.
The strategy we have adopted for analyzing the CFTR gene after FEB detection has evolved over time and is now as follows. The first step consists of applying, in both parents, a kit of 30 CFTR mutations (Elucigene CF30; Tepnel Diagnostics, Abingdon, Oxfordshire, UK), leading to a mutation detection rate of 88% in our population. If no mutation is identified by this technique, a screening of 13 exons of the CFTR gene is performed by DHPLC/sequencing or HRM/sequencing, leading to a mutation detection rate of 95%. If no mutation is detected in parental DNA samples, the molecular analysis is stopped, and the couple is informed of its residual risk of CF. If 1 mutation is identified in 1 parent by this strategy, the whole coding sequence of the gene is screened in the other parent by the same techniques and large rearrangements are searched for by CGH-array, which enables us to identify 99.5% of the CFTR mutations in our population. The first parental mutation found is also sought in the fetal DNA sample to exclude the diagnosis of CF if the fetus does not carry this mutation. If the complementary analysis does not identify a second mutation, genetic counseling is offered to the parents to inform them of the residual risk of CF in their child.
When both parents are found to be carriers of 1 CFTR mutation (and therefore prove to have a 1-in-4 risk of CF), genetic counseling is offered to the couple to explain the results and the possibility of a prenatal diagnosis. This consists of searching for their mutations in amniotic fluid cells. The fetus is considered to be CF-affected if it has inherited mutations from both parents. In this case, the option of a pregnancy termination is offered to the couple.
Other examinations
Chromosome analyses were performed on amniotic fluid cells using standard cytogenetic techniques with RHG-banding and GTG-banding. Detection of antibodies to cytomegalovirus and toxoplasmosis was performed with classical enzymatic immunoassay technologies.
Data collection
For each CFTR gene analysis made after sonographic detection of FEB, we recorded the following information: the date of the molecular testing, the place of residence of the mother/couple at the time of the examination, the result of the CFTR analysis, and the detailed ultrasound indications leading to a request for the molecular study.
To know the pregnancies’ outcomes, a questionnaire was sent to the gynecologists and/or sonographers who monitored the pregnancies approximately 6 months after the prenatal test. In France, gynecologists usually perform the complete follow-up of pregnancies and most of them make the deliveries. Moreover, gynecologists and/or sonographers receive a copy of the results of the tests they prescribed after FEB detection, as well as a report of delivery for each pregnancy they followed.
We distinguished 8 groups of possible associated disorders: CF, chromosomal abnormalities, viral infections, digestive tract malformations, cardiac malformations, vascular disorders, urinary tract malformations, and others.
Statistical analysis
Statistical analysis was done using EpiInfo software (version 6.04; Centers for Disease Control, Atlanta, GA). The significance level was set at P ≤ .05 for all analyses.
We described the type and frequency of disorders diagnosed in fetuses with FEB. We focused on CF and determined the prevalence of that disease and the carrier rate (with 95% confidence intervals [CIs]) and compared these figures with those observed in the general population by referring to the data of our NBS program over the same period. We also reported the type of CFTR mutations identified in those fetuses (severe or mild). Finally, we assessed the ability of ultrasonography in screening for CF in utero. This analysis was possible in our area, because both the NBS program and CFTR gene analysis after a diagnosis of FEB have been effective since the early 1990s. Combination of these data was used to assess the proportion of CF fetuses identified by ultrasonography over the study period.
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