Prenatal Screening For Cystic Fibrosis Research Articles

Issues in implementing prenatal screening for cystic fibrosis: Results of a working conference

PurposeTo summarize a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice. MethodsParticipants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed. ResultsJudged by published criteria, prenatal cystic fibrosis screening is suitable for introduction. Screening can be performed cost-effectively by identifying racial/ethnic groups at sufficient risk and then using either of two models for delivering laboratory services. Validated educational materials exist. Ethical issues are not unique. ConclusionsOnce adequate facilities for patient and provider education, testing, counseling, quality control, and monitoring are in place, individual programs can begin prenatal screening for cystic fibrosis. Genetics in Medicine, 1999:1(4):129–135.

Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case.

BACKGROUND: The potential of hyperechogenic fetal bowel to act as a hallmark for prenatal cystic fibrosis screening in the general population is controversial. METHODS: Our goal was to evaluate the...

Hereditary haemochromatosis mutation frequencies in the general population.

This study aims to expand our knowledge of the general population frequency of two mutations, C282Y and H63D, identified in the candidate gene for hereditary haemochromatosis, and to determine whether the testing can be performed using routinely obtained cheek-brush (buccal) samples. Banked buccal lysate samples, randomised and coded for anonymity, from a cohort of couples who underwent prenatal cystic fibrosis screening in Maine. A multiplex ARMS test was performed on buccal cell lysates to identify the two mutations. Genotype frequencies found among the 1001 subjects studied (502 women, 499 men) were: seven C282Y homozygotes, 22 C282Y/H63D compound heterozygotes, 97 C282Y heterozygotes, 17 H63D homozygotes, 246 H63D heterozygotes, and 612 individuals with no detectable mutation. The allele frequencies for C282Y and H63D were 0.066 and 0.151, respectively. Observed genotype frequencies in Maine are consistent with expectations and with consensus data from five smaller studies. Combined mutational analysis data indicate that homozygosity for C282Y (the genotype found in about 85% of subjects with diagnosed hereditary haemochromatosis) occurs in 51 per 10,000 white subjects of northern European heritage; the corresponding total hereditary haemochromatosis prevalence of about 60 per 10,000 is consistent with previous estimates. The study also confirms that H63D would not be useful in general population screening for hereditary haemochromatosis.

A multiplex ARMS test for 10 cystic fibrosis (CF) mutations: evaluation in a prenatal CF screening program.

In Maine, prenatal screening for cystic fibrosis (CF) is offered through primary care providers. Cheekbrush (buccal) samples are routinely tested for eight mutations by multiplex PCR amplification of five exons, followed by dot-blot hybridization with pooled allele-specific oligonucleotides (ASO). The ASO methodology is widely used and effective, but somewhat time and labor intensive when applied to CF carrier testing or couple-based prenatal screening in the general pregnant population. Amplification Refractory Mutation System (ARMS) is an improvement of the PCR that allows rapid detection of mutations involving single base changes or small deletions/insertions. In this study, two multiplex ARMS reactions are used to test for 10 common CF mutations. Clinical evaluation of the ARMS test includes a retrospective study of 140 banked samples (54 cell line, proficiency testing, and buccal controls; 86 clinical buccal samples) with known CF genotype (57 with CF mutations, 83 no mutation), followed by a prospective trial in which 309 buccal samples are analyzed con-currently using both methods. The success rate of the ARMS test in buccal lysates is comparable to the ASO method; all CF mutations are successfully identified. For testing nonsterile buccal lysates with low DNA concentrations, optimized performance in the ARMS method is obtained using Amplitaq Gold polymerase. The ARMS method developed is easy, rapid (1 day), and avoids the need for ASO probe labeling, dot-blotting and autoradiography. This study provides further evidence that ARMS methodology is suitable for clinical CF mutation analysis.

Prenatal screening for cystic fibrosis: An updated perspective

In U.S. white populations prenatal screening for cystic fibrosis can identify ≥60% of pregnancies in which the risk for an affected fetus is high. Such pregnancies occur when both the mother and the father carry cystic fibrosis mutations; about one screened couple per 1000 falls into this category. The risk of the fetus being affected is 1 in 4. Prenatal screening for cystic fibrosis compares favorably with prenatal screening for spina bifida and Down syndrome, with a similar detection rate, a much lower false-positive rate, and greater odds of being affected, given a positive result. Intervention trials in Europe and the United States provide documentation of efficacy. Larger-scale trials should now be encouraged in the United States to gain further insight into program design and case management, as a way to determine the feasibility of cystic fibrosis screening as part of routine prenatal care. (Am J Obstet Gynecol 1997;176:268-70.)

Prenatal screening for cystic fibrosis: 5 years' experience reviewed: Brock D.J.H. GBR Lancet 1996 347/8995 (148–150)

Prenatal screening for cystic fibrosis: 5 years' experience reviewed: Brock D.J.H. GBR Lancet 1996 347/8995 (148–150)

Prenatal Screening for Cystic Fibrosis

Abstract Summary Background Although several programmes of prenatal screening for cystic fibrosis have been completed and reported, there are still uncertainties about rates of take up and also about the action of parents identified as having a one-in-four risk of an affected child. I report 5 years' experience with the two-step and couple models of prenatal screening of cystic fibrosis. Methods Screening has been available at two antenatal clinics in Edinburgh, UK, since January, 1992, first on a research basis and then routinely. 25 000 couples have been screened. Findings Take-up rates for the two-step and couple models of delivery are very similar at about 70%. Take-up rates did not change when screening moved from a research to a routine service. Of 22 high-risk couples identified entirely through screening, 20 (91%) opted for prenatal diagnosis. Four couples returned for second and two for third monitored pregnancies. In all eight cases where affected fetuses were identified, pregnancy was terminated. Interpretation These data remove one of the few remaining obstacles to a general implementation of prenatal screening for cystic fibrosis.

Medical genetics: advances in brief: Prenatal screening for cystic fibrosis: 5 years' experience reviewed

Medical genetics: advances in brief: Prenatal screening for cystic fibrosis: 5 years' experience reviewed

Prenatal cystic fibrosis screening in a low-risk population undergoing chorionic villus sampling for fetal karyotyping.

Screening for cystic fibrosis (CF) has been offered to pregnant women seeking chorionic villus sampling (CVS) for prenatal chromosomal abnormality investigation. The mutation panel has increased over the years to include 8 mutations and can detect 65% of abnormal CF genes in the Italian population. Testing was offered to a total of 2214 consecutive pregnant women; 45 of them declined screening (take up rate: 98%). In 1055 of the 2169 pregnancies screened, the test was at first done on the fetus, while in the remaining cases both parents were investigated. Among parents 46 carriers were identified (2.1%), in 41 of whom the mutation was delta F508. In two couples both parents were heterozygous, and in one the fetus was affected and the pregnancy was terminated. Although CF testing offered to pregnant women undergoing invasive investigation such as CVS may not be the model for a mass screening, its very high effectiveness can represent an advantageous component of more comprehensive strategies.

Couple-based prenatal screening for cystic fibrosis in primary care settings.

This study examines a couple-based screening protocol for cystic fibrosis (CF) during pregnancy. The screening test is positive only when both partners carry an identifiable mutation. The risk for the fetus to be homozygous is 1 in 4, and definitive prenatal diagnostic testing can be offered. Between six and seven of every ten CF cases can be identified by testing for seven CF mutations. Couple screening for CF has not been evaluated in a decentralized health-care system. Office guides, informational materials, and consent forms were provided to 69 physicians in Maine. Women sent buccal samples to the study centre and brought sampling materials to their partners. Samples from both individuals were required. When a mutation was identified in the woman's sample, the partner's sample was tested. Screening results were reported to the physician. Standardized follow-up surveys were carried out in selected women, key office staff, and physicians. 1770 women and 1682 partners submitted samples. Testing was successfully completed for 1645 couples. Screening results were positive in one couple; the fetus was homozygous for CF. Physicians, office staff, and nearly all women were satisfied with the screening process. Couple screening for CF is feasible and acceptable in decentralized primary care settings.

Prenatal screening for cystic fibrosis: 5 years' experience reviewed

SummaryBackground Although several programmes of prenatal screening for cystic fibrosis have been completed and reported, there are still uncertainties about rates of take up and also about the action of parents identified as having a one-in-four risk of an affected child. I report 5 years' experience with the two-step and couple models of prenatal screening of cystic fibrosis.Methods Screening has been available at two antenatal clinics in Edinburgh, UK, since January, 1992, first on a research basis and then routinely. 25 000 couples have been screened.Findings Take-up rates for the two-step and couple models of delivery are very similar at about 70%. Take-up rates did not change when screening moved from a research to a routine service. Of 22 high-risk couples identified entirely through screening, 20 (91%) opted for prenatal diagnosis. Four couples returned for second and two for third monitored pregnancies. In all eight cases where affected fetuses were identified, pregnancy was terminated.Interpretation These data remove one of the few remaining obstacles to a general implementation of prenatal screening for cystic fibrosis.

Prenatal screening for cystic fibrosis: attitudes and responses of participants

A screening programme to detect cystic fibrosis heterozygotes has been running in the antenatal clinics of a major Edinburgh maternity hospital for more than 2 years. A questionnaire was used to assess participants' knowledge of the genetics of the disorder and their attitudes to being screened. The respondents were 64 female heterozygotes and 63 of their non-heterozygous male partners, 101 female controls and 100 male controls. Although the two groups of controls received far less direct information than the carriers and their partners, all four groups were well informed about the genetics of cystic fibrosis and the significance of being a gene carrier. A majority of each group felt that adequate information had been given in the information leaflet, that they understood the purpose of screening and that they were glad to have participated. There was a consensus that CF carrier testing should be routinely offered to pregnant women, and also that it should be available in family planning clinics and GP health centres, but not in schools.

Prenatal screening for cystic fibrosis: psychological effects on carriers and their partners.

This study aimed to assess the psychological impact of screening for cystic fibrosis (CF) carrier status in a population of pregnant women. A cohort of 1798 women, who accepted the offer of testing before 18 weeks of pregnancy, filled in a self administered questionnaire seeking information on their perceived risk of carrier status and their emotional response, as well as a general health questionnaire (GHQ). Sixty-four women identified as CF carriers had partners who received a negative test result. This group and their partners were assessed, together with selected controls, on four further occasions: (1) on receiving the carrier's positive test result; (2) on receiving the partner's negative test result; (3) six weeks later; (4) six weeks after delivery. The instruments used were the GHQ and the Symptom Rating Test (SRT). When compared to control subjects, carriers showed a significant increase in generalised psychological disturbance which could be attributed specifically to symptoms of anxiety and depression during the period (average four days) that they awaited their partner's test result. On receiving a partner's negative test result, the carriers returned to control levels and maintained this equilibrium. Although there was no significant difference in generalised psychological disturbance between partners and their selected controls, partners did become significantly more anxious and manifested feelings of inadequacy while awaiting their own test result. Both male partners and male control subjects were more likely to become anxious if their partner was distressed.

Prenatal Screening for Cystic Fibrosis

Prenatal Screening for Cystic Fibrosis

Prenatal screening for cystic fibrosis

Screening for carriers of CF (cystic fibrosis) is now possible but the best way of delivering such a service is unknown. In one model 4348 women attending antenatal clinics in an Edinburgh maternity hospital were invited to participate in a trial of prenatal screening. Mouthwash samples were tested for six CF alleles (85% of mutant genes) and when a woman was found to be a CF carrier her partner was also tested. Heterozygous couples were offered prenatal diagnosis. 609 (14%) women declined to enter the trial and another 574 (13%) were not screened, usually because of late booking. Among the remaining 3165 women there were 111 carriers of a CF gene (1 in 29). 4 of these 111 had carrier partners and these couples opted for prenatal diagnosis, the 1 pregnancy with an affected fetus being terminated. The psychological impact of screening was assessed by the general health questionnaire. There was a significant increase in stress at the time of the test result among women identified as carriers. However, this disappeared when their male partners tested normal and did not reappear later in the pregnancy. By providing time for couples to discuss the possibility of screening and by offering the test at a point (the antenatal booking clinic) at which most pregnant women are seen, this approach has advantages, provided that counselling is readily available.

Costs and benefits of prenatal screening for cystic fibrosis.

New tests promise to facilitate the prenatal detection of cystic fibrosis (CF), a fatal genetic disorder. This study examines the costs and benefits of prenatal screening and selective abortion using two types of tests: those based on restriction fragment-length polymorphisms (RFLPs), which can only be applied when genetic material is available from a CF-affected family member; and those based on probes for the newly discovered CF gene, which can be applied in the general population. When either type is applied in families of CF-affected children, even an expensive test produces substantial net benefits. Existing direct gene probe tests are not sensitive, although eventually they may become less expensive and more accurate than tests based on RFLPs. Even if these tests become highly accurate, the financial benefits of population-wide screening for CF are likely to be small or negative, particularly if testing does not lead to increases in the number of normal children as it decreases the number of births of CF-affected children. Because few children born in families without a history of CF have the disease, tests that are not perfectly specific will produce a large number of false-positive results, leading to the abortion of many normal fetuses.

Isoenzymes of alkaline phosphatase in amniotic fluid: Implications in prenatal screening for cystic fibrosis

Utilizing their differential susceptibilities to inhibitors and heat, we determined the amounts of the placental, liver, and fetal-intestinal isoenzyme forms of alkaline phosphatase in 143 samples of normal amniotic fluid obtained at 14 to 18 weeks' gestation (1). For reliable results, it was necessary to standardize inhibition profiles for each pure isoenzyme in amniotic fluid. Total activity and the absolute amounts of placental and fetal-intestinal activities were significantly related to gestational age (p less than 0.05). These relationships that were absent when activities were expressed as percentages of the total. The mean isoenzyme composition of the 143 samples, expressed as a percentage of total alkaline phosphatase activity, was: placental, 3.4%; liver, 9.8% (maximum, 47%); and fetal intestinal, 87% (minimum, 53%). The presence of phosphate in the assay medium (13.5 mmol/L) profoundly and differentially inhibited the isoenzymes of alkaline phosphatase and changed the inhibition profiles of the tissue-specific enzymes; thus, it would not be feasible to use inhibitors to differentiate the forms. We therefore propose a phosphate-free technique for quantifying the isoenzymes of alkaline phosphatase in amniotic fluid obtained at 14 to 18 weeks' gestation, to achieve the highest predictive values in a prenatal diagnostic test for cystic fibrosis.

Costs and benefits of prenatal screening for cystic fibrosis.

New tests promise to facilitate the prenatal detection of cystic fibrosis (CF), a fatal genetic disorder. This study examines the costs and benefits of prenatal screening and selective abortion using two types of tests: those based on restriction fragment-length polymorphisms (RFLPs), which can only be applied when genetic material is available from a CF-affected family member; and those based on probes for the newly discovered CF gene, which can be applied in the general population. When either type is applied in families of CF-affected children, even an expensive test produces substantial net benefits. Existing direct gene probe tests are not sensitive, although eventually they may become less expensive and more accurate than tests based on RFLPs. Even if these tests become highly accurate, the financial benefits of population-wide screening for CF are likely to be small or negative, particularly if testing does not lead to increases in the number of normal children as it decreases the number of births of CF-affected children. Because few children born in families without a history of CF have the disease, tests that are not perfectly specific will produce a large number of false-positive results, leading to the abortion of many normal fetuses.