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Biomedical subjects

D A Aitken

Publications and source records attributed to D A Aitken.

At least 37 records · Page 2Linked to original sources
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

Factors affecting women's knowledge of antenatal serum screening.

Antenatal screening for fetal anomaly is offered routinely in Glasgow. This study assessed pregnant women's knowledge of the test and implications of results. Questionnaires were completed by 574 women. Knowledge of the nature and uses of the test was superior to earlier studies Two-thirds knew that screening was undertaken for Down's syndrome, and 81% for spina bifida. The majority were aware of the sample used, ages invited and gestation at which it was undertaken. Knowledge of the likely results and implications was poorer. Three-quarters were unaware that 10% of results would suggest an increased risk. Half did not realise that positive results could occur without fetal abnormality, or negative results could be falsely reassuring. Socioeconomic deprivation was associated with poorer knowledge but not lower uptake. Written information was associated with superior knowledge and higher uptake. Leaflets should be provided prior to booking, at which time resultant queries can be answered.

Adolescent↗
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

Biochemical markers of trisomy 21 in amniotic fluid.

In a study of amniotic fluid from 91 Down's syndrome cases and 240 controls, we have shown that the median values of four biochemical markers (AFP, total hCG, free beta hCG, and unconjugated oestriol) in the amniotic fluid of pregnancies affected by Down's syndrome on the whole reflect those observed in the maternal serum of affected cases. The median MOM for AFP was lower than average (0.56), as was that for unconjugated oestriol (0.55), whilst those for total hCG (1.82) and free beta hCG (2.10) were increased on average. The width of the distribution of marker levels in amniotic fluid is similar to that in serum for free beta hCG and total hCG but between 1.5 and 2 times wider for unconjugated oestriol and AFP. Analysis of data by fetal sex showed a significantly higher median MOM in female control cases compared with male controls for the analytes free beta hCG, total hCG, and unconjugated oestriol, but not for AFP. Amongst the Down's syndrome cases, this trend was not statistically significant and we cannot confirm a previous study which reported that elevated levels of amniotic fluid total and free beta hCG were associated only with female fetuses.

Adult↗
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↗
PubMed1996

Urine free beta hCG and beta core in pregnancies affected by Down's syndrome.

Urine beta core was shown in recent studies to be markedly elevated in pregnancies affected by Down's syndrome in the late second trimester. Free beta human chorionic gonadotropin (hCG) has also been shown to be the most discriminatory maternal serum marker of Down's syndrome. Since free beta hCG is rapidly cleared from the maternal circulation, we have carried out a study to evaluate whether free beta hCG is elevated in the urine of pregnancies affected by Down's syndrome and to investigate whether urine beta core or urine free beta hCG may be used as possible screening markers. Urine samples from 29 cases of Down's syndrome, three cases of trisomy 18, and 400 control pregnancies were analysed for the two prospective markers. Results were corrected for urine concentration by expressing marker concentrations at a fixed creatinine concentration and then expressing the results as multiples of the median for unaffected pregnancies of the same gestation. The median value of beta core in the Down's syndrome pregnancies was 2.35 compared with 2.47 for free beta hCG. Free beta hCG distributions were closely similar to those in maternal serum. Using free beta hCG, we predict Down's syndrome detection rates of 58 per cent at a 5 per cent false-positive rate. Using beta core, however, this rate fell to 41 per cent. Measurement of free beta hCG in urine may present a feasible route for screening pregnant populations, particularly where community-based obstetric care is the norm and/or if early first-trimester screening becomes a reality.

Adult↗
PubMed1996

Prenatal diagnosis by enzyme analysis in 15 pregnancies at risk for the Lesch-Nyhan syndrome.

Fifteen pregnancies at risk for Lesch-Nyhan syndrome were investigated between 8 and 17 weeks' gestation by measurement of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and adenine phosphoribosyl transferase (APRT) enzyme activities in chorionic villus samples (cultured and uncultured) or in cultured amniotic fluid cells. Ten pregnancies had normal enzyme levels and a normal outcome while a further two predicted to be normal miscarried later in the pregnancy. Three pregnancies had low levels of residual HGPRT activity in chorionic villi. Comparable levels of residual activity in the index case in two pregnancies and in cells from the abortus in the third case confirmed that the pregnancies were affected.

Adenine Phosphoribosyltransferase↗
PubMed1996

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↗
PubMed1996

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↗
PubMed1995

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↗
PubMed1995

Ultrastructural study of the corneal epithelium in the recurrent erosion syndrome.

BACKGROUND: This study describes the adhesion systems in the corneal epithelium in the recurrent erosion syndrome and the mechanisms by which binucleate and multinucleate cells are formed within the epithelium. METHODS: Twenty five samples of sliding epithelium were obtained from 23 patients and were examined by conventional light and transmission electron microscopy. RESULTS: The separation of the anchoring system occurred either below the level of the anchoring plaques or at the level of the epithelial cell membrane. Normal and degenerate polymorphonuclear leucocytes were found within and between the epithelial cells and within the anchoring layer. Binucleate and multinucleate cells were found within all the layers of the epithelium as were cysts containing degenerate cellular material. CONCLUSION: The presence of leucocytes and degenerate epithelial cells within the sliding epithelium suggests that these are the source of the metalloproteinases which cleave Bowman's layer below the anchoring system. The formation of binucleate and multinucleate giant cells does not appear to occur by fusion of adjacent cells, but rather by nuclear indentation and cleaving due to an abnormal microtubular system in the cytoskeleton.

Adult↗
PubMed1994

Midtrimester chorionic villus sampling: an alternative approach?

OBJECTIVE: Our purpose was to audit midtrimester chorionic villus sampling after a positive maternal serum screening test for autosomal trisomy. STUDY DESIGN: From January 1990 until July 1993 chorionic villus sampling was offered to all screened positive women. RESULTS: Five hundred fifty-one mothers had chorionic villus sampling. The mean age was 31.7 years. The mean gestational age was 18.2 weeks. The mean time for direct karyotyping was 4.4 days and for culture results 20.2 days. Results were obtained in 99.6% of samples: direct plus culture results in 94%, direct results alone in 2.3%, and culture results alone in 3.3%. Fourteen pregnancies had abnormal karyotypes. There were five cases of placental mosaicism and one false-positive result. The loss rate was 0.4%. CONCLUSION: Midtrimester chorionic villus sampling, which is easier to perform than cordocentesis, provides a rapid and reliable karyotype. The complication rate is comparable to that of other invasive procedures.

Adult↗