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

OBJECTIVE: To summarise a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice. METHODS: Participants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed. RESULTS: Judged 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. CONCLUSIONS: Once adequate facilities for patient and provider education, testing, counselling, quality control, and monitoring are in place, individual programmes can begin prenatal screening for cystic fibrosis.

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

PURPOSE: To summarize a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice. METHODS: Participants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed. RESULTS: Judged 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. CONCLUSIONS: Once 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.

Prenatal screening for cystic fibrosis: an updated perspective.

In U.S. white populations prenatal screening for cystic fibrosis can identify > or = 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.

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.

Genealogical analysis of cystic fibrosis families and chromosome 7q RFLP haplotypes in the Hutterite Brethren.

In the 100-year period 1880-1980 the Hutterite population increased from about 442 to 23,000 individuals in North America. There are three endogamous subdivisions in this Caucasian genetic isolate. A total of 11 cystic fibrosis (CF) families from Canada and the United States were investigated, including at least two families from each of the three subdivisions, the Dariusleut, Lehrerleut, and Schmiedeleut. A study of RFLPs for the loci D7S8, D7S23, MET, and D7S18 (also called D7S16) in the region of the CF gene in 10 families shows considerable genetic variability. There were three different extended CF gene-region haplotypes on CF chromosomes (CF haplotypes), and there were 13 different extended CF gene-region haplotypes on normal chromosomes (normal haplotypes). The three CF haplotypes have different D7S23 and MET haplotypes. Parents who have the same CF haplotype are, on the average, more closely related than parents who have different haplotypes, but only within the same subdivision. A marriage node graph of 11 families illustrates the complexity of Hutterite genealogies. The frequency distribution of CF haplotypes in the Hutterite sample differs notably from those of larger agglomerates of family data from collaborative studies, with respect to D7S8, MET haplotypes, and D7S23 haplotypes. We propose that there were at least three CF carriers among the founders of the Hutterite population and that copies of a particular CF haplotype in current individuals are identical by descent. The alternative that one or more genetically distinguishable CF haplotypes resulted from recombination since the founding of the population is considered to be less likely.

Rare-event analysis methods for detection of fetal red blood cells in maternal blood.

Methods for analyzing very small subpopulations of cells ("rare-event analysis methods") are of interest in many areas of biology. In this paper we demonstrate the ability to detect one Rh-positive erythrocyte per 100,000 Rh-negative erythrocytes. This is the level needed to detect human fetal red blood cells in the maternal circulation in the case of fetal-maternal Rh-incompatibility. Erythrocytes stained with fluorescent immunobeads are more than 100 times as bright as the same cells stained by indirect immunofluorescence (or almost 40 times as bright as cells stained by the biotin-avidin technique). More importantly there is greater than a sevenfold increase in signal-to-noise (S/N) ratio, which proves critical in detecting very low frequency ("rare event") cell subpopulations. Although equal mixtures of positive and negative cells can easily be detected, positives cannot be easily distinguished from negatives when they are present in relative frequencies of 1:1000 or less as measured by either indirect immunofluorescence or biotin-fluorescent avidin labeling of D antigens. However, use of fluorescent immunobeads and high-speed flow cytometry allows detection of subpopulations of the same cells at relative frequencies of less than 1:100,000. Based on calibrations using free-fluorescent immunobeads, the average Rh-positive cell (when present in a relative frequency of 1:100,000) labeled with 36 +/- 19 fluorescent immunobeads. Rh-positive cells of relative frequencies 1:10,000 and 1:100,000 can be detected above background (Rh-negative red blood cells treated with the same amount of fluorescent immunobeads). Using defined mixtures of Rh-positive and negative cells, the expected numbers of positive cells were observed over a range of 1:100 to 1:100,000 relative Rh-positive cell frequencies. These methods should prove of general use in applications where original frequency information about rare cell subpopulations is important and would be lost if enrichment procedures were to be used.

Hormonal and cytogenetic studies in phenotypically female patients with gonadal dysgenesis.

In 4 cases of gonadal dysgenesis the clinical, hormonal, cytogenetic, and histological findings were correlated. There were 2 patients with 46,XY karyotype, one patient with 45,X Turner's syndrome and one patient with a 46,XX chromosome complement. All patients had streak gonads with ovarian stroma. In one phenotypically female 46,XY individual an involuted gonadoblastoma was found. Her testosterone was four-fold higher in gonadal vein blood compared to peripheral blood. Cytogenetic analysis of multiple tissues in both cases with the 46,XY karyotype greatly reduced the probability of mosaicism. In the patient with 45,X Turner's syndrome and in the one with 46,XX gonadal dysgenesis only peripheral blood cells were karyotyped and mosaicism was not further excluded by analysis of other tissues. The concentrations of steroid hormones in gonadal vein blood were low. The levels ranged as follows: estrone 41-98 pg/ml, estradiol 18-90 pg/ml, testosterone 37-294 ng/100 ml, dihydrotestosterone 13-22 ng/100 ml, and progesterone 0.3-1.5 ng/ml. It was concluded that gonadal streaks were similarly deficient in biosynthesis of steroid hormones despite different chromosomal complements.