Maternal serum alpha-fetoprotein levels in congenital nephrosis.
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Female↗
Biomedical subjects
J A Crossley
Publications and source records attributed to J A Crossley.
The pathophysiology of Down's syndrome pregnancies.
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Abortion, Induced↗
Dimeric inhibin A as a marker for Down's syndrome in early pregnancy.
BACKGROUND: In screening for Down's syndrome in the second trimester of pregnancy, the concentrations of alpha-fetoprotein, the beta subunit of human chorionic gonadotropin, and intact human chorionic gonadotropin in material serum are widely used markers. We investigated a new marker, dimeric inhibin A, and compared its predictive value with that of the established markers. METHODS: Serum samples were obtained at 7 to 18 weeks of gestation from 58 women whose fetuses were known to be affected by Down's syndrome, 32 whose fetuses were affected by trisomy 18, and 438 whose fetuses were normal, and the samples were analyzed for each marker. Individual serum concentrations of each marker were converted to multiples of the median value at the appropriate length of gestation in the women with normal pregnancies, and rates of detection of Down's syndrome by screening for inhibin A in various combinations with the other markers were estimated by multivariate analysis. RESULTS: In the women with fetuses affected by Down's syndrome, the serum inhibin A concentrations were 2.06 times the median value in the women with normal pregnancies (P < 0.001). This compared with 2.00 times the median for the beta subunit of human chorionic gonadotropin, 1.82 times the median for intact human chorionic gonadotropin, and 0.72 for alpha-fetoprotein. The serum concentrations of inhibin A in the women with fetuses affected by Down's syndrome did not appear to be significantly elevated above normal until the end of the first trimester and were not significantly different from normal in the women with fetuses affected by trisomy 18 (P = 0.17). The rate of detection of Down's syndrome was 53 percent and the false positive rate was 5 percent when alpha-fetoprotein, the beta subunit of human chorionic gonadotropin, the maternal age were used together as predictors. The detection rate increased to 75 percent when inhibin A was added (P = 0.002). CONCLUSIONS: In the second trimester of pregnancy, measuring inhibin A in maternal serum, in combination with measurements of alpha-fetoprotein and beta subunit of human chorionic gonadotropin, significantly improved the rate of detection of Down's syndrome.
Biomarkers↗
Insulin-dependent diabetes mellitus and prenatal screening results: current experience from a regional screening programme.
From around 91,000 women having routine prenatal screening for Down's syndrome and neural tube defects between July 1992 and October 1995, 261 women were identified as having insulin-dependent diabetes mellitus (IDDM). Alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) levels were reduced in these women, with median levels of 0.89 and 0.91 multiples of the median (MOM), respectively. The IDDM patients had a median weight which was 6 kg heavier than that of non-IDDM women. After correction for maternal weight, the AFP and hCG levels in the IDDM patients were 0.98 and 0.92 MOM, respectively. In routine practice, using results which were not weight-corrected, the IDDM women were neither over- nor under-represented in the high-risk group for Down's syndrome, but showed a tendency to be under-represented in the high-risk group for neural tube defects.
Adolescent↗
Heat-stable and immunoreactive placental alkaline phosphatase in maternal serum from Down's syndrome and trisomy 18 pregnancies.
Placental alkaline phosphatase (ALP) activity was investigated in second-trimester maternal sera from 37 pregnancies with Down's syndrome, 28 pregnancies with trisomy 18, and in a series of 497 controls using a fluorimetric heat inactivation assay and specific immunoassay. After conversion of individual analyte values to multiples of the normal gestational median (MOM), no significant differences in total or placental ALP activities were found in the trisomy 21 or trisomy 18 cases (P > 0.01). In the Down's syndrome pregnancies, total ALP activity was 0.93 MOM, heat-stable ALP activity was 1.09 MOM, and placental ALP (by immunoassay) 0.96 MOM. In the trisomy 18 cases, total ALP activity was 0.90 MOM, heat-stable ALP activity was 0.79 MOM, and placental ALP (by immunoassay) 0.94 MOM. We conclude that neither total nor placental ALP activity is a useful marker for Down's syndrome or trisomy 18 screening.
Alkaline Phosphatase↗
Analysis of maternal serum alpha-fetoprotein and free beta human chorionic gonadotrophin in the first trimester: implications for Down's syndrome screening.
The aim of this study was to determine the maternal population, pregnancy, serum alpha-fetoprotein (AFP) and free beta subunit of human chorionic gonadotrophin (F beta hCG) parameters in a large series of women attending prenatal clinics before 15 weeks' gestation and to assess the practical problems of population screening for Down's syndrome in the first trimester using these markers. Serum samples were collected from 8600 women attending prenatal clinic booking visits. Maternal serum AFP and F beta hCG medians were calculated for each day of gestation (49-104 days), using both dates and ultrasound estimates of gestation. The effects of maternal weight, twin pregnancies, and threatened abortion on AFP and F beta hCG levels were analysed. The median age of the population was 27.1 years and the median weight 62.1 kg. Twenty-six per cent of samples were collected before 70 days and 50 per cent before 78 days' gestation. Eighty-nine per cent of all samples had gestational estimates by dates, 60 per cent by ultrasound and 52 per cent by both dates and ultrasound. The AFP median was 5 kU/l at 49 days, 5.9 kU/l at 70 days, and 17.9 kU/l at 100 days. The peak median F beta hCG level was 66.4 ng/ml at 64 days, falling to 20.6 ng/ml at 100 days' gestation. Both AFP and F beta hCG levels showed log Gaussian distributions but the standard deviation for AFP was 20 per cent greater than that found in the second trimester. AFP and F beta hCG levels showed an inverse relationship with maternal weight and were increased in twin pregnancies (1.68 and 1.97 multiples of the median, respectively). AFP and F beta hCG can be readily measured in a large screening population in the first trimester. Down's syndrome screening protocols based on these markers could be refined by the use of gestations in individual days but AFP is likely to be a less effective marker and detection rates are likely to be lower than in the second trimester. To realize the potential of first-trimester screening, more women should be encouraged to attend the prenatal clinic in early pregnancy and ultrasound dating should be carried out for all pregnancies at this stage.
Abortion, Threatened↗
First trimester biochemical screening for trisomy 21: the role of free beta hCG, alpha fetoprotein and pregnancy associated plasma protein A.
The potential efficacy of screening for trisomy 21 in the first trimester, using maternal serum markers alpha fetoprotein, free beta human chorionic gonadotropin, unconjugated oestriol and pregnancy associated plasma protein A, was studied in an unselected population of women between the seventh and fourteenth week of gestation. Using a combination of alpha fetoprotein and free beta human chorionic gonadotropin, 53% of affected pregnancies could be identified at a false positive rate of 5%. Unconjugated oestriol and pregnancy associated plasma protein A levels were lower in cases of trisomy 21, but their inclusion with other markers did not significantly improve detection rate. Monitoring the same pregnancies also in the second trimester showed that screening in the first trimester identified the same cases as in the second. We conclude that first trimester screening using free beta human chorionic gonadotropin and alpha fetoprotein, is a viable possibility and will lead to detection rates in excess of 50%. Prospective studies are needed to confirm these observations.
Adolescent↗
Impact of a regional screening programme using maternal serum alpha fetoprotein (AFP) and human chorionic gonadotrophin (hCG) on the birth incidence of Down's syndrome in the west of Scotland.
OBJECTIVES: To evaluate the impact of a large scale population screening programme on the birth incidence of Down's syndrome in the west of Scotland over a 12 month period. METHODS: Biochemical screening for Down's syndrome using maternal serum alpha fetoprotein, chorionic gonadotrophin, and maternal age was offered to a pregnant population of 37,226 women in the west of Scotland between 1991 and 1992. The combined risk of Down's syndrome pregnancy was reported for each of the 30,084 women who opted for screening. RESULTS: When a threshold risk of 1:220 was used 1523 women (5.1% of the screened population) were assigned to the high risk group, of whom 1070 (70%) proceeded to diagnostic amniocentesis or midtrimester chorionic villus sampling. When multiple sources of ascertainment were used 37 Down's syndrome pregnancies were identified within the screened population, 26 (70%) of which were within the high risk group and 21 (57%) of which were prenatally diagnosed. In addition, three Down's syndrome pregnancies were diagnosed by first trimester chorionic villus sampling before biochemical screening. A further 10 Down's syndrome pregnancies were identified at birth, eight to women who had not had a screening test and two to women who had moved into the area, making a total of 50 Down's syndrome pregnancies in the whole pregnant population of 37,226. Thus the potential prenatal detection rate in the screened population was 70% (26/37), the actual prenatal detection rate in the screened population was 57% (21/37), and the overall prenatal detection rate in the total (screened and unscreened) population was 48% (24/50). CONCLUSION: Biochemical screening for Down's syndrome is practical and effective in routine clinical practice, enabling women to make an informed choice about prenatal diagnosis and providing better use of scarce resources when a suitable protocol is applied to the whole pregnant population. Its maximum potential for the reduction of the birth incidence of Down's syndrome is limited by incomplete uptake of screening and compliance with diagnostic testing in the high risk group.
Adolescent↗
Second-trimester unconjugated oestriol levels in maternal serum from chromosomally abnormal pregnancies using an optimized assay.
Second-trimester unconjugated oestriol (UE3) levels were measured retrospectively in maternal serum from 78 chromosomally abnormal pregnancies and 390 matched controls using a radioimmunoassay kit (Amersham AMERLEX-M) optimized for use in the second trimester. Reduced levels of UE3 were found in a group of 49 Down's syndrome pregnancies with a median UE3 level of 0.79 multiples of the median (MOM) of the controls. Four trisomy 18 pregnancies had UE3 levels less than 0.7 MOM. There was a highly significant level of correlation between alpha-fetoprotein (AFP) and UE3 levels in the controls (r = 0.25, p < 0.01), the Down's syndrome pregnancies (r = 0.44, p < 0.01), and the other chromosome abnormalities (r = 0.61, p < 0.01). When used as an additional marker to AFP and human chorionic gonadotrophin in screening for Down's syndrome, UE3 does not appear to add to the sensitivity of such screening.
Chromosome Aberrations↗
First-trimester biochemical screening for fetal chromosome abnormalities and neural tube defects.
Alpha-fetoprotein (AFP), unconjugated oestriol (UE3), intact human chorionic gonadotrophin (intHCG), and the free beta subunit of chorionic gonadotrophin (F beta HCG) were investigated in a series of 21 chromosomally abnormal and 14 open neural tube defect pregnancies ascertained from a series of 14,000 prospectively collected maternal serum samples at 6-14 weeks' gestation. In 16 cases of Down's syndrome, significant reductions were found for AFP (0.65 multiples of the normal median) and UE3 (0.67 MOM). IntHCG levels were unaltered (0.97 MOM) but a significant increase was found for F beta HCG (1.96 MOM). Significant correlations were found for AFP and UE3 in the controls and for intHCG and F beta HCG in both the control and the Down's syndrome pregnancies. In a group of five trisomy 18 pregnancies, median MOMs were for AFP 0.71, for UE3 0.34, for intHCG 0.27, and for F beta HCG 0.15. None of 13 pregnancies with open neural tube defects at 8-13 weeks gestation had elevated maternal serum AFP levels, whereas matched second-trimester samples from the same pregnancies at 16-18 weeks gestation all had significantly elevated AFP levels. Thus, biochemical screening for chromosome abnormalities may be practicable in the first trimester using free beta human chorionic gonadotrophin in combination with AFP and maternal age. However, a separate screening protocol using AFP at 15-18 weeks gestation would still be required for effective detection of neural tube defects.
Biomarkers↗
Dual analyte immunoassay in neural tube defect and Down's syndrome screening: results of a multicentre clinical trial.
We report a multicentre clinical field trial of a novel dual analyte enzyme immunoassay method for the simultaneous measurement of alpha-fetoprotein (AFP) and free beta-human choriogonadotropin (hCG) in the same microtitre well. The assay was shown to have good technical performance in the hands of all trial centres, with between assay coefficients of variation better than 10% for both analyte across the whole of the assay ranges. The method compared well with single analyte measuring procedures and produced acceptable performance as judged by external quality assurance criteria. Recovery of added analyte and analyte dilution curves also showed acceptable performance. In clinical evaluation of a large set of neural tube defect cases, good clinical discrimination from unaffected cases was observed using AFP. With over 150 Down's syndrome cases, the combination of AFP and free beta hCG confirmed the high detection rates achievable using this marker combination, with detection rates in excess of 70% in early gestation. We conclude that the combination of clinically superior markers coupled with technologically innovative assay design will lead to more efficient Down's screening programmes.
Adolescent↗
Variation in the levels of pregnancy-specific beta-1-glycoprotein in maternal serum from chromosomally abnormal pregnancies.
Human pregnancy-specific beta-1-glycoprotein (SP1) was assayed retrospectively in stored maternal serum (MS) samples from 82 chromosomally abnormal pregnancies and 377 matched controls. The median MSSP1 concentration in 48 Down's syndrome pregnancies was significantly elevated at 1.17 multiples of the control median (MOM), and significantly reduced (0.5 MOM) in a group of eight cases of unbalanced translocations. There was no significant difference in median SP1 concentrations in cases of trisomy 18, trisomy 13, balanced translocations, or sex chromosome abnormalities. A comparison with human chorionic gonadotrophin results in the same series of samples indicates that SP1 is a less sensitive predictor of Down's syndrome pregnancies.
Chorionic Gonadotropin↗
Prenatal screening for chromosome abnormalities using maternal serum chorionic gonadotrophin, alpha-fetoprotein, and age.
Human chorionic gonadotrophin (hCG) levels were assayed retrospectively in stored maternal serum samples from 78 chromosomally abnormal pregnancies and 410 controls matched for gestation and maternal age. The median serum hCG concentration in 49 pregnancies with Down's syndrome was significantly elevated, at 2.18 multiples of the normal median. Significantly reduced hCG concentrations were found in a group of four trisomy 18 pregnancies (all less than 0.4 multiples of the median). Eight cases of unbalanced chromosome rearrangements appeared to show some lowering of hCG levels, while there was no significant difference in the levels in the cases of trisomy 13, balanced translocations, and sex chromosome abnormalities. Maternal serum hCG alone is a better indicator of Down's syndrome pregnancies than maternal age or maternal serum alpha-fetoprotein (AFP), either individually or in combination, and provides a further virtually independent measure of risk. On the basis of our findings, screening for Down's syndrome using hCG and AFP results combined with maternal age risks is predicted to result in a higher detection rate (57 per cent) for a lower false-positive rate (5.0 per cent) than would be attainable by combined AFP and age screening (37 per cent detection at a 6.6 per cent false-positive rate).
Chorionic Gonadotropin↗
Estimating the risk of a fetal autosomal trisomy at mid-trimester using maternal serum alpha-fetoprotein and age: a retrospective study of 142 pregnancies.
Risks appropriate for mid-trimester prenatal screening for autosomal trisomies have been estimated from a combination of maternal age and maternal serum (MS) alpha-fetoprotein (AFP) levels at 16-20 weeks gestation. Published data on the frequency of Down's syndrome births relative to maternal age were modified to include the additional age-related frequency of trisomy 18 and trisomy 13 cases to provide an overall risk for an autosomal trisomy at mid-trimester. MSAFP results from a retrospective study of 142 affected (114 trisomy 21, 19 trisomy 18, and 9 trisomy 13) and 113,000 unaffected pregnancies were converted to multiples of the appropriate gestational median (MOM). The AFP levels in the autosomal trisomy pregnancies were found to be significantly reduced at 0.72 MOM of the unaffected pregnancies. Risks (likelihood ratios) were derived from the overlapping log Gaussian distributions for affected and unaffected pregnancies and combined with maternal age risks to give the overall odds of an affected pregnancy. A mid-trimester cut-off risk of 1:280 gave an estimated 37 per cent detection rate for autosomal trisomies in the west of Scotland population for a follow-up (false-positive) rate of 6.6 per cent. These figures compare with a 30 per cent detection and 6.7 per cent false-positive rate if age 35 years and over is used as the sole criterion for selection of at-risk pregnancies.
Adolescent↗
Amniotic fluid alpha-fetoprotein, gamma-glutamyltranspeptidase, and autosomal trisomies.
Alpha-fetoprotein (AFP) concentration and gamma-glutamyltranspeptidase (GGT) activity have been analysed in amniotic fluid from a series of 65 pregnancies with autosomal trisomies. AFP values were reduced on average to 60 per cent of normal in cases of trisomy 21, but were not significantly different from normal in cases of trisomies 18 and 13. GGT activities were uniformly lower (44 per cent of normal) for all types of autosomal trisomy. A review of the literature indicates that over 85 per cent of Down's pregnancies but only 39 per cent of trisomy 18 and 13 pregnancies have amniotic fluid AFP levels below the normal median value, while the corresponding figures for GGT are 91 per cent for Down's syndrome and 96 per cent for trisomies 18 and 13.
Amniotic Fluid↗
Congenital diaphragmatic defects and maternal serum alphafetoprotein.
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Biomarkers↗
Linkage analysis using multiple Xq DNA polymorphisms in normal families, families with the fragile X syndrome, and other families with X linked conditions.
Multipoint linkage analysis was undertaken with eight Xq cloned DNA sequences which identify one or more restriction fragment length polymorphisms in 26 families. These families comprise seven phase known normal families with three or more males in the third generation, seven families segregating for haemophilia B, one large family with dyskeratosis congenita, and 11 families with the fragile X syndrome. Phase known meioses informative for three or more loci supported the order centromere--DXYS1--DXS107--DXS102, DXS51--F9--FRAXA--DXS15, DXS52, F8--Xqter in each group of families studied. One of the normal families was segregating for protan colour blindness and showed a phase known recombination which would support the order centromere--F9--DXS52--CBP--Xqter. With the exception of DXYS1, all of these sequences have been localised to Xq27----qter by in situ hybridisation or hybridisation to Xq fragment panels, and on this basis should lie within 20 cM of one another. No recombination was observed between the sequences localised to Xq28, namely DXS52, F8, and DXS15 (between DXS15 and DXS52 Z = 12.25 at theta = 0 with confidence limits of 0 to 5 cM). However, an excess of recombination was apparent in the region of FRAXA with maximal lod scores as follows: F9 versus FRAXA (Z = 2.05, theta = 0.19), DXS52 versus FRAXA (Z = 1.85, theta = 0.26), and DXS15 versus FRAXA (Z = 1.33, theta = 0.27). No consistent differences were observed in the frequency of recombination when families with the fragile X syndrome were compared with normal families or families segregating for other X linked conditions. These results are compared with other published work and support the conclusion that although measurable linkage exists between these flanking markers and FRAXA, the intervals as measured by the frequency of meiotic recombination will seriously limit their clinical usefulness.
Chromosome Mapping↗
The poly(adenylic acid) sequence of mouse globin messenger RNA.
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Adenosine Monophosphate↗