[show abstract][hide abstract] ABSTRACT: Of the 65 328 pregnancies of South Australian mothers screened by the South Australian Maternal Serum Antenatal Screening (SAMSAS) Programme between 1 January 1991 and 31 December 1997, 3431 (5.25%) were declared at increased risk of fetal Down syndrome. Fetal or neonatal karyotype was determined in 2737/3431 (79.8%) of these pregnancies, including 16 with early fetal loss. Interrogation of the database of the South Australian Neonatal Screening Service showed 643 live-born infants whose phenotype was not subsequently questioned among the 694 pregnancies whose karyotype was not determined. Of the remaining 51/3431 pregnancies, 19 ended in early fetal loss without karyotyping and no newborn screening or other records could be found for 32 cases. The 129 instances of abnormal karyotype found were Down syndrome (84), trisomy 18 (four), trisomy 13 (three), triploidy (two), female sex chromosome aneuploidy (six) and male sex chromosome aneuploidy (five), inherited balanced rearrangements (19), mosaic or de novo balanced abnormalities (four) and unbalanced karyotypes (two). In the pregnancies declared at increased risk of fetal Down syndrome, only the karyotype for Down syndrome occurred with a frequency greater than that expected for the general, pregnant population.
[show abstract][hide abstract] ABSTRACT: To describe the impact of maternal serum screening on the birth prevalence of Down's syndrome and on the use of amniocentesis and chorionic villus sampling in South Australia.
A descriptive population-based study.
South Australia (population 1.48 million persons; approximately 20,000 births per year).
Women who had births or terminations of pregnancy with Down's syndrome in 1982-1996, women who had maternal serum screening in 1991-1996, amniocentesis or chorionic villus sampling in 1986-1996.
Analysis of data from multiple sources on maternal serum screening, amniocentesis and chorionic villus sampling, births and terminations of pregnancy.
Total prevalence and birth prevalence of Down's syndrome each year in 1982-1996; proportion of pregnant women using maternal serum screening in 1991-1996, and proportion using amniocentesis and chorionic villus sampling by indication in 1986-1996, by age group.
Use of maternal serum screening for Down's syndrome increased from 17% when introduced in 1991 to 76% of women who gave birth in 1996. Between 1982 and 1986 and 1996, terminations of pregnancy for fetal Down's syndrome increased from 7.1 % to 75% and the birth prevalence of Down's syndrome fell by 60% from 1.05 to 0.42 per 1,000 births, against the background of an increase in total prevalence due to increasing maternal age. The use of amniocentesis increased from 5.8% in 1991 to 10.1% in 1996 mainly due to the increase among women younger than 35 years with maternal serum screening as the main reason. The increasing chorionic villus sampling rate among younger women stabilised at 0.4%, while the rate among older women decreased from 11.0% to 7.4%.
The introduction of maternal serum screening in South Australia has resulted in increased use of any prenatal testing for Down's syndrome from about 7% (mainly older women having amniocentesis or chorionic villus sampling) to 84% of women (about 8% having direct amniocentesis or chorionic villus sampling and 76% having maternal serum screening first). This has resulted in a significant fall in the birth prevalence of Down's syndrome. maternal serum screening was the first indication of Down's syndrome for about half the terminations of pregnancy for Down's syndrome in 1993-1996, including three quarters of those in younger women.
BJOG An International Journal of Obstetrics & Gynaecology 01/2001; 107(12):1453-9. · 3.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: We aimed to examine the longitudinal relationship between lipoprotein(a) and haemoglobin A1c, albumin excretion rate, and puberty in peripubertal children with insulin-dependent diabetes. A total of 114 patients aged 11.5 +/- 3.6 years (mean (SD)) were followed prospectively for 15.2 +/- 2.8 months. Lipoprotein(a), apolipoproteinB-100, haemoglobin A1c, mean overnight albumin excretion rate and Tanner stage were determined at the beginning and end of the study period. Lipoprotein(a) and apolipoproteinB-100 were measured using nephelometry. This method was correlated with radioimmunoassay and there was no significant change in mean bias during the study. Lipoprotein(a) fell significantly over time (214, (152, 276); 160 (84, 236) mg l-1 geometric mean (0.95 confidence intervals), p < 0.001); apolipoproteinB-100 did not change. Lipoprotein(a) and apolipoproteinB-100 did not differ in 233 cross-sectional controls of similar age. The change in lipoprotein(a) did not correlate with a small fall in haemoglobin A1c or with overnight albumin excretion rate, Tanner stage or insulin dose. Separate analysis of male and female patients and prepubertal and pubertal patients continued to show a significant fall in lipoprotein(a) independent of change in haemoglobin A1c or albumin excretion rate. Likewise, 53 patients with a change in haemoglobin A1c of greater than 1%, and 20 patients who progressed from normal albumin excretion rate to albumin excretion rate above the 95th centile, showed no relationship between lipoprotein(a) and haemoglobin A1c or albumin excretion rate. In conclusion, longitudinal changes in lipoprotein(a) do not relate to metabolic control or early changes in albuminuria in young patients with insulin-dependent diabetes.
Diabetic Medicine 06/1995; 12(6):508-12. · 3.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the performance and impact of a two tier neonatal screening programme for cystic fibrosis based on an initial estimation of immunoreactive trypsinogen followed by direct gene analysis.
Four year prospective study of two tier screening strategy. First tier: immunoreactive trypsinogen measured in dried blood spot samples from neonates aged 3-5 days. Second tier: direct gene analysis of cystic fibrosis mutations (delta F508, delta I506, G551D, G542X, and R553X) in samples with immunoreactive trypsinogen concentrations in highest 1% and in all neonates with meconium ileus or family history of cystic fibrosis.
South Australian Neonatal Screening Programme, Adelaide.
All 88,752 neonates born in South Australia between December 1989 and December 1993.
Neonates with two identifiable mutations were referred directly for clinical assessment and confirmatory sweat test; infants with only one identifiable mutation were recalled for sweat test at age 3-4 weeks. Parents of neonates identified as carriers of cystic fibrosis mutation were counselled and offered genetic testing.
Identification of all children with cystic fibrosis in the screened population.
Of 1004 (1.13%) neonates with immunoreactive trypsinogen > or = 99th centile, 912 (90.8%) had no identifiable mutation. 23 neonates were homozygotes or compound heterozygotes; 69 carried one identifiable mutation, of whom six had positive sweat tests. Median age at clinical assessment for the 29 neonates with cystic fibrosis was 3 weeks; six had meconium ileus and two had affected siblings. 63 neonates were identified as carriers of a cystic fibrosis mutation. Extra laboratory costs for measuring immunoreactive trypsinogen and direct gene analysis were $A1.50 per neonate screened.
This strategy results in early and accurate diagnosis of cystic fibrosis and performs better than screening strategies based on immunoreactive trypsinogen measurement alone.
[show abstract][hide abstract] ABSTRACT: To determine serum lipoprotein(a) in a large sample of IDDM and control children and to examine a possible association with puberty.
Serum lipoprotein(a), apoB-100, and apoA-I were measured under identical conditions in 170 Caucasian children with IDDM aged 12.3 +/- 3.59 yr and 233 Caucasian control children aged 13.6 +/- 1.12 yr. Patients with persistent microalbuminuria were excluded. Lipoprotein(a), apoB-100, and apoA-I were measured by nephelometry using a specific monoclonal antibody. Pubertal assessment was performed using Tanner staging and testicular volume measurement.
Lipoprotein(a) was higher in the IDDM than control group (geometric mean 237 mg/L, 25-75th percentile 134-465 vs. 172 [99-316] mg/L, P = 0.0008). When analyzed according to pubertal stage, only pubertal and postpubertal patients had higher levels than control subjects (265 [148-560] vs. 174 [101-320] mg/L, P = 0.0001), with prepubertal patients showing no difference. Pubertal and postpubertal patients showed both higher lipoprotein(a) (P = 0.01) levels and higher albumin excretion rates (P = 0.02) than prepubertal patients, correcting for the other variable. Lipoprotein(a) was not related to HbA1c, albumin excretion rate, duration, age, sex, mean arterial pressure, or a family history of premature coronary artery disease in the IDDM group. Lipoprotein(a) was not higher in patients with overnight albumin excretion rate above the 95th percentile but below the microalbuminuric range. ApoB-100 did not differ between IDDM and control children. ApoA-I was significantly lower in the IDDM group (1.04 [0.94-1.17] vs. 1.21 [1.10-1.31] g/L; P < 0.0001).
Pubertal and postpubertal IDDM patients have higher serum lipoprotein(a) than Caucasian control subjects. Our findings suggest a rise in lipoprotein(a) may occur during puberty in IDDM. Longitudinal studies are required to clarify the relationship between lipoprotein(a), albumin excretion rate, and puberty.
Diabetes Care 06/1993; 16(6):869-73. · 7.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: A coated microtiter-well, enzyme-linked immunometric assay for quantifying immunoreactive trypsinogen in dried blood spots was modified to use time-resolved fluorescence of europium in place of end-point enzymatic color development as the quantification step. The streptavidin-horseradish peroxidase and color development solutions supplied as packaged reagents were replaced by europium-labeled avidin, and the signal was developed with commercially available enhancement solution and read by time-resolved fluorescence. The change of label from enzyme to europium increased the dynamic range of the assay by about 5-fold, reduced the detection limit 10-fold, and halved the intra- and interassay imprecision. The improved analytical precision and stability of the modified assay resulted in a more precise description of the population distribution of immunoreactive trypsinogen values in newborns, showing less variance in the upper centiles. This effect is of paramount importance when using this assay for neonatal screening for cystic fibrosis.
[show abstract][hide abstract] ABSTRACT: A prenatal screening programme for Down's syndrome potentially detecting 76 per cent of affected pregnancies in the South Australian general population at an amniocentesis rate of 3.9 per cent was designed following analysis of mid-trimester serum samples from 57 women who carried an affected fetus. This equates to one affected pregnancy being detected for 41 chromosomal analyses performed. For the experimental series, 75.4 per cent of affected pregnancies were detected, while 4.1 per cent of control specimens produced estimated risk odds consistent with further action. A maternal risk odds of birth of a Down's syndrome fetus of 1:420 was taken as the decision value, which is the prevalence of Down's syndrome births to 35-year-old mothers in South Australia. This screening performance was achieved by investigating combinations of serum analytes not previously reported and by refining the calculation of maternal risk odds to include selective weighting of indicator analytes. Combination of the measurements of free alpha-subunits and beta-subunits of chorionic gonadotrophin, alpha-fetoprotein, unconjugated oestriol, and placental lactogen was found to be most effective in indicating Down's syndrome fetuses. In all combinations of analytes tested, replacing the measurements of free alpha-subunits and free beta-subunits of chorionic gonadotrophin with the measurement of intact chorionic gonadotropin produced a less effective screen.
[show abstract][hide abstract] ABSTRACT: The feasibility of extending second-trimester maternal blood screening for Down syndrome so as to include screening for trisomy 18 was examined using stored maternal serum samples collected for neural tube-defect screening. There were 12 samples from trisomy 18 pregnancies and 390 controls. The median maternal serum concentration of alpha-fetoprotein, free alpha-subunit human chorionic gonadotrophin, free beta-subunit human chorionic gonadotrophin, intact human chorionic gonadotrophin, total estriol, unconjugated estriol, estradiol, human placental lactogen, and progesterone were lowered in those pregnancies affected by trisomy 18 when compared with unaffected pregnancies matched for racial origin, maternal age, gestational age, and sample-storage duration. At an estimated odds risk of 1:400, 83.3% of affected pregnancies were detected using an algorithm which combines the maternal age-related risk with the maternal serum concentrations of unconjugated estriol, free alpha-subunit human chorionic gonadotrophin, free beta-subunit human chorionic gonadotrophin, estradiol, and human placental lactogen. The associated false-positive rate was 2.6%. At high risk odds of 1:10, the detection rate was 58.3%, with an associated false-positive rate of 0.3%. beta-Subunit human chorionic gonadotrophin and unconjugated estriol were the most powerful discriminators. It is possible to incorporate into existing Down syndrome screening programs an algorithm for detecting trisomy 18 with high sensitivity and specificity.
The American Journal of Human Genetics 12/1991; 49(5):1025-33. · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the effectiveness of a two tier neonatal screening strategy for cystic fibrosis, which combines estimation of immunoreactive trypsinogen followed by direct gene analysis in dried blood spot samples collected at age 5 days.
Prospective study of two tier screening strategy. The first tier of testing immunoreactive trypsinogen concentration was measured in dried blood spot samples from neonates aged 4-5 days. In the second tier direct gene analysis to detect cystic fibrosis mutations deltaF508 and deltaI506 was performed in those blood spot samples which produced the highest 1% of immunoreactive trypsinogen values. Direct gene analysis was also performed on blood spot samples from infants with suspected or confirmed meconium ileus, regardless of the immunoreactive trypsinogen value.
The South Australian Neonatal Screening Programme, operating from the department of chemical pathology at Adelaide Children's Hospital. Subjects--All 12,056 neonates born in South Australia between December 1989 and June 1990. No selection criteria were applied.
All infants found to have two recognised cystic fibrosis mutations on direct gene analysis were referred directly for clinical management, and those with one recognised cystic fibrosis mutation were recalled for a sweat test; their families were given genetic counselling.
Direct or exclusion of cystic fibrosis by sweat testing of neonates identified as being at high risk of cystic fibrosis on screening and of those at minimum risk but whose subsequent clinical history raised suspicion about the disease.
Of the 12,056 infants screened, 11,907 (98.8%) were reported as "cystic fibrosis not indicated" on the basis of low immunoreactive trypsinogen values. Of the 148 (1.23%) infants with raised immunoreactive trypsinogen values and one (0.008%) with meconium ileus, 132 (1.09%) were reported as cystic fibrosis not indicated, four (0.033%) were identified as having cystic fibrosis, and 13 (0.108%) were recalled for sweat testing after direct gene analysis for the presence of the deltaF508 and deltaI506 cystic fibrosis mutations. No cases of affected infants are known to have been missed to date.
The strategy of measurement of immunoreactive trypsinogen followed by direct gene analysis is a highly specific neonatal screen for cystic fibrosis, requiring only 2.8 families to be contacted for every case of cystic fibrosis diagnosed.