Search PubMed⌕ Search

Biomedical subjects

J A Crossley

Publications and source records attributed to J A Crossley.

At least 19 recordsLinked to original sources
PubMed2002

Maternal smoking: age distribution, levels of alpha-fetoprotein and human chorionic gonadotrophin, and effect on detection of Down syndrome pregnancies in second-trimester screening.

OBJECTIVES: To study the levels of maternal serum alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) in the second trimester in smokers and non-smokers with unaffected and Down syndrome pregnancies; to examine the rate of smoking in different maternal age groups in a population having routine prenatal screening; and to assess the effect of smoking on the detection rates for Down syndrome and corresponding false-positive rates, both overall and in different maternal age groups. METHODS: Information on maternal smoking status, maternal age and serum marker levels was collected from case note searches and the screening programme database on 2272 unaffected singleton pregnancies, 36 unaffected twin pregnancies and 103 singleton Down syndrome pregnancies. RESULTS: In unaffected pregnancies the smokers had a median age 3.3 years less than the non-smokers, while in the Down syndrome cases the corresponding age difference was 2.0 years. Median analyte levels in multiples of the median (MoM) in the unaffected singleton pregnancies were, for non-smokers: AFP=0.97, hCG=1.04; and for smokers, AFP=1.04, hCG=0.80. In the Down syndrome pregnancies the medians were, for non-smokers: AFP=0.69, hCG=2.49; and for smokers, AFP=0.70, hCG=1.53. Correction for smoking status gave median MoMs of 1.0 for both AFP and hCG in the unaffected pregnancies in both smokers and non-smokers. In the Down syndrome cases the corrected medians were, for non-smokers: AFP=0.67, hCG=2.29; and for smokers, AFP=0.73, hCG=1.99. Before correction for maternal smoking the overall detection rate for Down syndrome was 66.7% with a false-positive rate of 6.2%. After correction the detection rate was 67.7% with a false-positive rate of 4.9%. Between the smoking and non-smoking groups there was a significant difference in the detection rate (37.5% versus 76.0%) and the false-positive rate (1.8% versus 8.1%), which disappeared after correction for smoking status (detection rate 62.5% versus 69.3%, false-positive rate 3.9% versus 5.4%). No evidence of a lower incidence of Down syndrome in smokers was found. CONCLUSIONS: While correcting AFP and hCG results for maternal smoking status will have little impact on the overall detection rate for Down syndrome, it may reduce the false-positive rate and will improve the accuracy of the risks given to individual women.

Adult↗
PubMed2002

Temporal changes in maternal serum biochemical markers of trisomy 21 across the first and second trimester of pregnancy.

BACKGROUND: Many maternal serum markers show concentration changes in Down's syndrome pregnancies but the magnitude of the change in median marker levels varies with gestation. To date these changes have not been accurately specified. METHODS: The trends in marker median levels between 6 and 20 weeks of gestation were examined for alphafetoprotein (AFP), free beta human chorionic gonadotrophin (Fbeta-hCG), total human chorionic gonadotrophin (ThCG) and pregnancy-associated plasma protein A (PAPP-A) by a meta-analysis of data obtained from our collaborative studies and routine screening programmes for Down's syndrome over a 10-year period. Data were available from between 709 and 1082 Down's syndrome pregnancies and from between 14607 and 153909 unaffected pregnancies for each marker. The median multiple of the median (MoM) and mean log10MoM for each marker at each completed week of gestation were estimated and the trend with gestation smoothed using a weighted least squares regression model. RESULTS: The gestational ages at which maximum separation of marker levels occurred, comparing affected and unaffected pregnancies, and the respective regressed median MoMs and mean log10MoMs, were: for AFP at 16 weeks, 0.72 MoM, -0.14288log10MoM; for Fbeta-hCG at 15 weeks, 2-24MoM, 0.35034 log10MoM; for ThCG at 16 weeks, 1.93 MoM, 0.28548 log10MoM, as well as before 8 weeks (<0.65 MoM, -0.18853 log10MoM); and for PAPP-A before 8 weeks, <0.33 MoM, -0.47727 log10MoM. CONCLUSION: There is significant temporal variation in mean log10MoM values for the screening markers investigated. Screening algorithms, modified to take account of this variation, should allow more accurate gestation-specific risks to be calculated in individual pregnancies.

Biomarkers↗
PubMed2001

Growth hormone binding protein in normal and aneuploid pregnancy: a paradoxical decrease in trisomy 18.

OBJECTIVE: To explore whether abnormalities in growth hormone binding protein (GHBP) may underlie the growth restriction associated with fetal aneuploidy. DESIGN: A retrospective casecontrol study. SETTING: Monash Medical Centre. Clayton, Victoria, Australia. POPULATION: Twenty-one trisomy 18, and 30 trisomy 21 pregnancies, and 170 chromosomally normal pregnancies at 15-18 weeks of gestation representing three to five controls per case matched for source, gestation and duration of storage. METHODS: GHBP was measured using a ligand immunofunctional assay RESULTS: In the chromosomally normal pregnancies GHBP levels decreased slightly but significantly across the narrow gestational window studied. Compared with controls, levels of GHBP, expressed as median (95% CI) multiples of the median (MoM). in the trisomy 21 pregnancies were similar, 1.0 (0.92-1.39) MoM and 1.27 (1.04-1.50) MoM, respectively; P = 0.061 (Mann-Whitney U test) but were significantly reduced in the trisomy 18 pregnancies, 0.68 (0.5 1-0.84) MoM: P = 0.0014 (Mann-Whitney U test). CONCLUSIONS: These data suggest that decreased levels of maternal growth hormone binding protein, and by implication growth hormone receptor complement, may underlie the early severe growth restriction that is characteristic of trisomy 18.

Carrier Proteins↗
PubMed2000

Is maternal serum total hCG a marker of trisomy 21 in the first trimester of pregnancy?

In a study of 130 first trimester cases of trisomy 21 and 959 controls we have shown that the median MoM for alpha-fetoprotein (AFP) is lower (0.82) and that for total human chorionic gonadotrophin (hCG) is higher (1.31) than in the control group. For AFP 15.3% of cases were below the 5th centile and for total hCG 19. 8% were above the 95th centile. The median shift observed for AFP and total hCG is poorer than that for pregnancy associated plasma protein-A (PAPP-A) or free beta-hCG and together with maternal age, AFP and total hCG could only be expected to detect 40% of cases. In combination with PAPP-A, total hCG would identify 52% of cases, somewhat less than the 67% observed with free beta-hCG and PAPP-A. However, we have demonstrated for total hCG a significant temporal change in median MoM with gestational age. Before 70 days the median MoM was less than 0.5, between 70 and 83 days this increased to 1.13, and between 84 and 97 days this increased to 1.52. This median shift has significant implications for interpreting previous studies and even more significant implications for detection rates. When population parameters specific to the gestational age in question are used, detection rates with total hCG and PAPP-A increase from 47% at 70-83 days to 60% at 84-97 days. This observation explains much of the confusion around total hCG in the first trimester and shows the importance of selecting analyte pairs and population parameters appropriate to the time in gestation when screening is performed.

Adolescent↗
PubMed1999

Second-trimester pregnancy associated plasma protein-A levels are reduced in Cornelia de Lange syndrome pregnancies.

Maternal serum samples were collected from 19 pregnancies which resulted in the birth of a child with the classical Cornelia de Lange syndrome phenotype ascertained by careful clinical review. Using specific immunoassays, the serum levels of pregnancy associated plasma protein-A, free-beta human chorionic gonadotrophin and inhibin A were investigated. Pregnancy associated plasma protein-A was detectable in all cases but the levels were significantly reduced in second-trimester maternal serum from 18 affected pregnancies. Expressed as multiples of the median (MOM), the results ranged from 0.03 MOM to 0.71 MOM with an overall median value of 0.21 MOM (Mann-Whitney p<0.001). From these data it is possible to estimate a probability that any given level of this serum marker is associated with an affected pregnancy. One further sample taken in the first trimester from an affected pregnancy at 11 weeks' gestation had a normal pregnancy associated plasma protein-A level (1.22 MOM). Less markedly reduced levels were found for free beta human chorionic gonadotrophin and inhibin A. We conclude that second-trimester maternal serum pregnancy associated plasma protein-A measurements may be of value as an adjunct to ultrasonography in the prenatal diagnosis of Cornelia de Lange syndrome. A table of likelihood ratios is presented.

Chorionic Gonadotropin, beta Subunit, Human↗
PubMed1999

Second trimester levels of pregnancy associated plasma protein-A in cases of trisomy 18.

In a study of 70 cases of trisomy 18 and 450 matched controls in the second trimester we have measured the maternal serum levels of the analytes alpha feto protein (AFP), free beta-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A). We have found the median multiple of the median (MoM) of maternal serum free beta-hCG to be significantly lower (0.327) than normal, as was the level of AFP (0.600). Levels of PAPP-A were reduced even further (0.108). Of the markers associated with trisomy 18 at this time PAPP-A was the most discriminatory, being lower than the 5 per cent centile of normal in 93 per cent of cases, compared with 57 per cent of cases for free beta-hCG and 32 per cent of cases for AFP. Combining free beta-hCG and PAPP-A or all three markers with maternal age would have the ability to detect 74 per cent of cases at a 0.5 per cent false positive rate (or 64 per cent at a 0.1 per cent false positive rate). Unlike in cases of trisomy 21, the low PAPP-A values observed in the first trimester are continued into the second trimester. Whether the good discriminatory power of PAPP-A can be realized in second trimester screening programmes will depend on developing two stage screening algorithms. This approach is unlikely to be better than the excellent detection rates achievable with free beta-hCG, PAPP-A and nuchal translucency in the first trimester.

Adult↗
PubMed1998

Evolution of an inhibin A ELISA method: implications for Down's syndrome screening.

The development of a sensitive and specific enzyme-linked immunoassay (ELISA) for inhibin A stimulated the observation that inhibin A was a useful prenatal marker of Down's syndrome. Modifications of that ELISA, in terms of preassay sample treatment, detection methods and standard preparation, were subsequently introduced to improve assay performance and reduce costs. These modified formats have been validated and reported. We describe the modifications in detail, explaining the rationale for each, and report the results of a study directly comparing the various ELISA formats in terms of assay performance when applied to clinical samples and ability to differentiate between normal and Down's syndrome pregnancies. A format involving sample pretreatment with sodium dodecylsulphate at 100 degrees C was found to give better assay performance and a modest improvement in discrimination between Down's syndrome samples and controls, and we recommend this format for use by other investigators.

Down Syndrome↗
PubMed1998

Inhibin-B and pro-alphaC-containing inhibins in amniotic fluid from chromosomally normal and Down syndrome pregnancies.

In second-trimester Down syndrome pregnancies, levels of inhibin-A (the alpha-betaA dimer) in maternal serum and amniotic fluid (AF) are significantly higher and lower than in normal pregnancy, respectively. Since AF also contains inhibin-B (the alpha-betaB dimer) and precursor inhibins, we have examined whether the secretion of these inhibin isoforms may also be altered in association with Down syndrome. AF from 45 Down syndrome and 150 chromosomally normal pregnancies between 16 and 19 weeks' gestation were analysed, blinded to whether the sample was from a Down syndrome or a normal pregnancy. The median (10th-90th percentiles) inhibin-B level in the control pregnancies increased from 310.0 (80.8-1112.5) pg/ml at 16 weeks to 459.5 (193.7-1386.8) pg/ml at 19 weeks' gestation. The corresponding figures for precursor inhibins (pro-alphaC inhibins) were 541.8 (206.9-1322.8) pg/ml at 16 weeks and 1391.8 (433.3-2652.6) pg/ml at 19 weeks. Expressed as multiples of the median (MOM), the levels of inhibin-B and pro-alphaC inhibins in the Down syndrome samples were 0.85 and 0.79, respectively. Neither was significantly different from the controls. These data suggest that, of the three inhibin subunits, abnormal production or secretion of the inhibin betaA-subunit may underlie the decreased inhibin-A levels previously observed in Down syndrome. Confirmation of this by quantitative assessment of the inhibin subunit messenger ribonucleic acids would now be useful.

Amniocentesis↗
PubMed1997

Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters.

OBJECTIVE: To monitor changes with gestation in levels of alpha-fetoprotein (AFP), free beta human chorionic gonadotrophin (F beta hCG) and pregnancy associated plasma protein-A (PAPP-A) in Down's syndrome pregnancies and to compare risks estimated in the first trimester with those obtained by routine screening in the second trimester for the same pregnancies. DESIGN: In each of 47 Down's syndrome pregnancies two maternal serum samples were obtained, one in the first trimester and one in the second trimester. Comparison of marker levels with 10,600 first trimester controls and a smaller sample of second trimester controls allowed case identification criteria based on optimum marker combinations to be developed and compared directly between trimesters. SETTING: Biochemical genetics laboratory. RESULTS: F beta hCG was an effective marker of Down's syndrome in both the first and second trimesters. PAPP-A levels were significantly reduced in trisomy 21 pregnancies in the first trimester only. Using a population model, these two markers in combination with maternal age gave an overall detection rate of 55% for a 5% false positive rate in the first trimester. For the paired first and second trimester samples, three of six cases classified as low risk by routine second trimester screening were classified as high risk by the first trimester screening protocol of F beta hCG/PAPP-A/maternal age. However, fifteen cases identified as high risk by routine second trimester screening were classified as low risk in the first trimester, a net loss in detection of 12 cases by first trimester screening. CONCLUSION: The data suggest that first trimester detection rates for Down's syndrome using a combination of F beta hCG and PAPP-A may vary with gestation and will be lower than those currently obtained by routine second trimester screening with AFP/hCG.

Biomarkers↗
PubMed1997

Maternal serum inhibin-A in pregnancies complicated by insulin dependent diabetes mellitus.

We have examined whether insulin dependent diabetes mellitus (IDDM) affects maternal serum levels of inhibin-A, a recently described prenatal marker of Down's syndrome, by comparing levels in 169 women with IDDM with levels in 432 nondiabetic pregnant women between 15 and 20 weeks of gestation. There was a small but significant increase in the inhibin-A level in the diabetic women only when levels were corrected for maternal weight: median MoM 1.17 (P < 0.01 vs controls, Student's t test). The underlying mechanism for this elevation in pregnancies complicated by IDDM currently remains obscure.

Biomarkers↗
PubMed1997

Dimeric inhibins in amniotic fluid, maternal serum, and fetal serum in human pregnancy.

Using new specific and sensitive enzyme-linked immunosorbent assays for inhibin A and inhibin B, we measured these proteins in amniotic fluid (AF), maternal serum (MS), and umbilical cord serum in normal pregnancies. Inhibin A levels in AF rose from a median (10-90th percentile) level of 615 (158.2-1124.6) pg/mL at 14 weeks to 1336.0 (489.4-2084.1) pg/mL at 20 weeks, and inhibin B rose from 216.6 (67.4-554.6) to 1078.2 (439.3-2482.2) pg/mL over the same period. In MS, inhibin A levels fell from a median (10-90th percentile) level of 177.5 (101.4-290.7) pg/mL at 10 weeks to a nadir of 111.9 (59.5-200.3) pg/mL at 17 weeks, rising again to 180.3 (74.1-327.2) pg/mL at 20 weeks. No inhibin B was detectable in MS. In 47 pairs of matched samples (14-16 weeks gestation) there was no correlation of inhibin A levels in AF with those in MS (r = 0.19; P > 0.05). In 45 term umbilical cord serum samples, no dimeric inhibin was detectable in serum from female babies, but inhibin B was detectable in male sera; the median (10-90th percentile) concentration was 167.4 (111.2-224.8) pg/mL. These data suggest that for the gestation periods studied, although the placenta secretes inhibin A, another source, probably the fetal membranes, secretes both inhibin A and inhibin B. Further, the presence of inhibin B in male fetuses is consistent with a testicular origin, suggesting that inhibin B may be important in the development of the fetal hypothalamo-pituitary-testicular axis.

Amniocentesis↗
PubMed1997

Amniotic fluid inhibin-A in chromosomally normal and Down's syndrome pregnancies.

Recently, inhibin-A has been shown to be a useful new prenatal marker of Down's syndrome, significantly increasing detection rates. While the placenta is believed to be the major source of inhibin in pregnancy, there are actually very limited data available on specific inhibin dimers in pregnancy. Using a sensitive and specific ELISA we have measured the inhibin-A content of amniotic fluid (AF) to investigate further the biology of inhibin-A in chromosomally normal and abnormal pregnancies. AF from 51 Down's syndrome and 161 chromosomally normal pregnancies between 16 and 19 weeks of gestation were analysed, blinded as to whether the sample was from a Down's syndrome or normal pregnancy. There were no sex differences in inhibin-A content in either the control or Down's syndrome pregnancies. The median (10-90th percentiles) inhibin-A level in the control pregnancies increased from 339.6 (175.2-649.1) pg/ml at 16 weeks to 592.9 (256.4-1027.3) pg/ml at 19 weeks of gestation. The median (95% confidence interval) inhibin-A in the Down's syndrome pregnancies, expressed as multiples of the median (MoM) to correct for gestation, was 0.77 (0.68-0.89) MoM, significantly lower than the controls (P < 0.001, Mann-Whitney U test). We believe that these data are compatible with more than one source of inhibin-A in pregnancy and suggest that the fetal membranes may be contributing significantly to AF inhibin-A content. Further, our data would suggest that the endocrine function of the placenta and the other inhibin source(s) are differentially regulated.

Amniotic Fluid↗
PubMed1997

Neural tube defects/alpha-fetoprotein/Down's syndrome screening.

Maternal serum screening for alpha-fetoprotein, initially as an indicator of open neural tube defects and more recently combined with other pregnancy-specific markers as an indicator of Down's syndrome, is an established part of prenatal testing. Recent work has focused on the role of folic acid in the primary prevention of neural tube defects and on the search for a genetic component in the aetiology of neural tube defects. Potential new markers of Down's syndrome have been identified in maternal serum and urine. Nuchal translucency measurements by ultrasound and the identification of appropriate maternal serum markers in the first trimester offer the prospect of screening earlier in pregnancy.

Biomarkers↗
PubMed1997

Biochemical markers of trisomy 21 and the pathophysiology of Down's syndrome pregnancies.

Using biochemical and immunocytochemical methods, we have investigated endogenous levels of various markers in tissues obtained from 67 Down's syndrome pregnancies after therapeutic abortion in the second trimester and in corresponding tissues from unaffected abortuses. Alpha-fetoprotein (AFP), intact and free beta human chorionic gonadotrophin (hCG), pregnancy-specific beta-1 glycoprotein (SP-1), placental alkaline phosphatase (PALP), pregnancy-associated plasma protein A (PAPP-A), and gamma glutamyl transferase (GGT) were investigated in placental tissue; AFP and GGT in fetal liver; and GGT in fetal intestine. The results indicate that maternal serum levels of placental products reflect those found in the placenta: intact hCG, free beta hCG, and SP-1 levels were elevated in Down's syndrome pregnancies, while PAPP-A and PALP levels were little changed. This suggests that membrane passage of these markers is not affected but there is altered synthesis of hCG and SP-1. AFP levels were strikingly elevated in placental homogenates and unchanged in liver homogenates from Down's syndrome pregnancies, while the levels in maternal serum were reduced, pointing to a possible transport defect specific to AFP. GGT levels were high in placenta and liver from Down's syndrome pregnancies but low in fetal intestine.

Biomarkers↗
PubMed1996

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↗