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Biomedical subjects

A Kennard

Publications and source records attributed to A Kennard.

At least 19 recordsLinked to original sources
PubMed1998

Routine ultrasound scanning for congenital abnormalities.

Screening has been defined as "the systematic application or a test or enquiry, to identify individuals at sufficient risk of a specific disorder to benefit from further investigation or direct preventive action, among persons who have not sought medical attention on account of symptoms of that disorder" (Wald, N.J. 1994. J. Med. Screen. 1:76). The purpose of screening is to benefit the individuals being screened. The early detection of abnormalities should not be an end in itself, and the value of a screening approach needs to be determined before it is introduced into practice. Ultrasound as a means of screening for fetal abnormalities has not been adequately assessed even though it is widely used in this way. To assess its value it is helpful to classify abnormalities that can be detected on the basis of the clinical usefulness of doing so. To this end we propose four categories similar to those independently suggested by the Royal College of Obstetricians and Gynaecologists Working Party on Ultrasound Screening for Fetal Abnormalities. Four groups were specified: (A) major abnormalities--death inevitable, (B) abnormalities associated with long-term handicap, (C) abnormalities potentially amenable to intrauterine treatment, and (D) fetal conditions that require immediate postnatal investigation and/or treatment. For each abnormality, the screening detection and false-positives need to be estimated together with the medical and financial costs of screening, particularly those arising from findings of uncertain or little medical consequence that may lead to worry and further unnecessary obstetric intervention.

Congenital Abnormalities↗
PubMed1997

Antenatal screening for Down's syndrome.

BACKGROUND: In 1968 the first antenatal diagnosis of Down's syndrome was made and screening on the basis of selecting women of advanced maternal age for amniocentesis was gradually introduced into medical practice. In 1983 it was shown that low maternal serum alpha fetoprotein (AFP) was associated with Down's syndrome. Later, raised maternal serum human chorionic gonadotrophin (hCG), and low unconjugated oestriol (uE3) were found to be markers of Down's syndrome. In 1988 the three biochemical markers were used together with maternal age as a method of screening, and this has been widely adopted. PRINCIPLES OF ANTENATAL SCREENING FOR DOWN'S SYNDROME: Methods of screening need to be fully evaluated before being introduced into routine clinical practice. This included choosing markers for which there is sufficient scientific evidence of efficacy, quantifying performance in terms of detection and false positive rates, and establishing methods of monitoring performance. Screening needs to be provided as an integrated service, coordinating and managing the separate aspects of the screening process. SERUM MARKERS AT 15-22 WEEKS OF PREGNANCY: A large number of serum markers have been found to be associated with Down's syndrome between 15 and 22 weeks of pregnancy. The principal markers are AFP, hCG or its individual subunits (free alpha- and free beta-hCG), uE3, and inhibin A. Screening performance varies according to the choice of markers used and whether ultrasound is used to estimate gestational age (table 1). When an ultrasound scan is used to estimate gestational age the detection rate for a 5% false positive rate is estimated to be 59% using the double test (AFP and hCG), 69% using the triple test (AFP, hCG, uE3), and 76% using the quadruple test (AFP, hCG, uE3, inhibin A), all in combination with maternal age. Other factors that can usefully be taken into account in screening are maternal weight, the presence of insulin dependent diabetes mellitus, multiple pregnancy, ethnic origin, previous Down's syndrome pregnancy, and whether the test is the first one in a pregnancy or a repeat. Factors such as parity and smoking are associated with one or more of the serum markers, but the effect is too small to justify adjusting for these factors in interpreting a screening test. URINARY MARKERS AND FETAL CELLS IN MATERNAL BLOOD: Urinary beta-core hCG has been investigated in a number of studies and shown to be raised in pregnancies with Down's syndrome. This area is currently the subject of active research and the use of urine in future screening programmes may be a practical possibility. Other urinary markers, such as total oestriol and free beta-hCG may also be of value. Fetal cells can be identified in the maternal circulation and techniques such as fluorescent in situ hybridisation can be used to identify aneuploidies, including Down's syndrome and trisomy 18. This approach may, in the future, be of value in screening or diagnosis. Currently, the techniques available do not have the performance, simplicity, or economy needed to replace existing methods. DEMONSTRATION PROJECTS: Demonstration projects are valuable in determining the feasibility of screening and in refining the practical application of screening. They are of less value in determining the performance of different screening methods. Several demonstration projects have been conducted using the triple and double tests. In general, the uptake of screening was about 80%. The screen positive rates were about 5-6%. About 80% of women with positive screening results had an invasive diagnostic test, and of those found to have a pregnancy with Down's syndrome, about 90% chose to have a termination of pregnancy. ULTRASOUND MARKERS AT 15-22 WEEKS OF PREGNANCY: There are a number of ultrasound markers of Down's syndrome at 15-22 weeks, including nuchal fold thickness, cardiac abnormalities, duodenal atresia, femur length, humerus length, pyelectasis, and hyperechogenic bowel. (ABSTRA

Biomarkers↗
PubMed1996

Effect of allowing for ethnic group in prenatal screening for Down's syndrome.

We conducted a study to investigate ethnic group differences in levels of serum markers used in screening for Down's syndrome [serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha- and free beta-hCG, and dimeric inhibin-A], to estimate the extent to which maternal weight differences between ethnic groups explain these differences, and to estimate the effect of adjusting for ethnic group and maternal weight on screening performance. Serum measurements were taken from women who were screened prenatally for Down's syndrome. AFP, uE3, and hCG concentrations were available from 9462 white, 4215 black, and 4392 South Asian women with singleton pregnancies without Down's syndrome or neural tube defects between 15 and 22 weeks' gestational age. Frozen serum samples were available from a subset of 922 white, 449 black, and 135 South Asian women and were used for measurement of free alpha-hCG, free beta-hCG, and inhibin. Values were expressed as multiples of the median (MOM) for women of the same gestational age. There were statistically significant differences in the serum marker levels between ethnic groups that were not explained by differences in maternal weight. The main differences were found in black women compared with white women; black women had serum AFP levels 22 per cent higher (95 per cent confidence interval 20-24 per cent), total hCG levels 19 per cent higher (16-22 per cent), and free beta-hCG levels 12 per cent (3-21 per cent) higher. The other differences were less than 10 per cent. Adjusting for ethnic group only had a small estimated effect on screening performance: a maximum of about 0.5 per cent extra detection at a 5 per cent false-positive rate. At a fixed risk cut-off level, the false-positive rate will not be materially different between different ethnic groups. Adjusting serum markers for ethnic groups improves Down's syndrome screening performance to a very small extent. It is worthwhile because of its established value in AFP screening for open neural tube defects.

Asian People↗
PubMed1996

Empirical validation of risk screening for Down's syndrome.

OBJECTIVE: To validate individual risk estimates in antenatal serum screening for Down's syndrome. METHODS: Women screened for Down's syndrome using maternal serum alpha fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophin (hCG) with maternal age (the triple test) or AFP, uE3, free beta subunit and free alpha subunit of hCG with maternal age (the quadruple test) were grouped according to their predicted risk of having an affected pregnancy. The mean predicted risk in each category was then compared with the observed prevalence based on the number of affected and unaffected pregnancies in each category. SUBJECTS: About 100,000 pregnant women screened for Down's syndrome from 1989 to 1995. RESULTS: There was close agreement between the predicted term risk and the prevalence at birth for both the triple test and the quadruple test. For example, with the quadruple test the predicted risk in the highest risk group was 1 in 3.3 and the prevalence was 1 in 2.6; in the lowest risk group these were 1 in 3000 and 1 in 2300 respectively. CONCLUSION: Risk estimates based on multiple marker screening for Down's syndrome are accurate. The technique used to demonstrate this is simple and offers a useful empirical check on screening performance.

Adult↗
PubMed1995

Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotropin.

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.

Adult↗
PubMed1995

First trimester serum screening for Down's syndrome.

Screening for Down's Syndrome has been shown to be effective at 10 weeks of pregnancy. A multicentre study (the first trimester serum screening study) has shown that there are two biochemical markers of choice at this time in pregnancy, namely pregnancy associated placental protein A (PAPP-A) and the free beta-sub-unit of human chorionic gonadotrophin (free beta-hCG). When used together with maternal age these two biochemical markers have an estimated detection rate of 62% and a 5% false-positive rate. The results are consistent with those obtained from a systematic review of the world literature. Other markers are less predictive of Down's syndrome though there is still some uncertainty over the value of dimeric inhibin-A at 10 weeks of pregnancy. Nuchal translucency measurement, from an ultrasound examination performed at about 10 weeks of pregnancy, is associated with Down's syndrome and is emerging as an important potential screening marker. At present there is uncertainty over its quantitative performance and performance when combined with biochemical markers. The resolution of these issues is currently the subject of active research. Ten week screening for Down's syndrome is an advance that is now technically possible though there is still insufficient information to justify its use in routine screening practice.

Biomarkers↗
PubMed1994

Value of maternal serum unconjugated oestriol measurement in prenatal screening for Down's syndrome.

We compared the medical and financial cost-effectiveness of prenatal serum screening for Down's syndrome using maternal age, serum alpha-fetoprotein and human chorionic gonadotrophin with and without the use of unconjugated oestriol. The use of unconjugated oestriol is medically more cost-effective than screening without it at all levels of detection. The actual performance depends on whether gestational age is estimated using 'dates' or an ultrasound scan. At a detection rate of 60 per cent, the proportion of unaffected fetal losses per case diagnosed at amniocentesis is about 22 per cent less if gestational age is estimated using dates (time since the first day of the last menstrual period) and about 47 per cent less if it is based on an ultrasound scan examination. At this detection rate, the inclusion of unconjugated oestriol increases costs by about 2k pounds per case diagnosed (36k pounds instead of 34k pounds) if gestational age is estimated using dates, but it is no more expensive if gestational age is measured from an ultrasound scan examination (indeed, it is more cost-effective at detection rates above 60 per cent). Since there is little change in the financial cost with the inclusion of unconjugated oestriol, for the improved medical performance of screening, it is worthwhile including it in the screening test.

Amniocentesis↗
PubMed1994

First trimester biochemical screening for Down's syndrome.

A number of biochemical markers in maternal serum have been proposed for first trimester screening for Down's syndrome. The most promising four are pregnancy associated plasma protein A (PAPP-A), the free beta sub-unit of human chorionic gonadotrophin (hCG) (free beta glycoprotein sub-unit), unconjugated oestriol (uE3) and alpha-fetoprotein (AFP). An analysis of the published literature suggests that 70% of affected pregnancies could be detected for a 5% false-positive rate if the four markers are used in combination with maternal age and assumed to be independent measures of risk. This is a level of performance that is similar to second trimester screening. It is, however, a tentative estimate because of the assumption of independence and the possibility that the effect may be exaggerated by publication bias. Further research is needed before such screening is introduced. Other first trimester markers which have been studied include total hCG, free alpha-hCG, CA125, PLAP and SP1 but they either look unpromising or there are too few data available to determine their value. The timing of antenatal diagnosis by means of chorion villus sampling should be delayed until after 10 weeks of pregnancy because of the risk of causing limb defects. Screening need not, therefore, be performed before about 9 or 10 weeks of pregnancy.

Abortion, Induced↗
PubMed1993

Biparietal diameter and crown-rump length in fetuses with Down's syndrome: implications for antenatal serum screening for Down's syndrome.

OBJECTIVES: 1. To compare the ultrasound biparietal diameter and crown-rump length of fetuses with and without Down's syndrome in the first half of pregnancy; 2. To investigate the effect of estimation of gestational age using either measure on the detection rate of serum screening for Down's syndrome. DESIGN: Matched case-control study. Cases were singleton Down's syndrome pregnancies with a biparietal diameter or a crown-rump length recorded. Five controls were matched to each case on: medical centre; the date of the ultrasound scan examination (within two years); gestational age measured as the number of days since the first day of the last menstrual period; and the ultrasound measure used (ie the biparietal diameter (the measure of choice), or the crown-rump length otherwise). If a woman had a serum screening test for Down's syndrome, the biparietal diameter or crown-rump length measurement had to be taken prior to the screening test so that the result of the test could not influence whether a scan was performed. SETTING: Ten antenatal screening centres in seven countries in Europe and North America. SUBJECTS: Two hundred and one women with singleton Down's syndrome pregnancies and 1005 women with unaffected singleton pregnancies. RESULTS: The median biparietal diameter of fetuses with Down's syndrome was identical to that among the controls (median difference 0.0 mm, 95% confidence intervals (CI) -0.5 to 0.5 mm). The estimates of gestational age based on biparietal diameter yielded a median gestational age less than that based on the women's last menstrual period: three days less for cases and two days less for controls; small but statistically significant differences probably reflected a minor systematic difference in the conversion of a biparietal diameter to a gestational age estimate. The median crown-rump length of fetuses with Down's syndrome was also identical to that among controls (median difference 0.0 mm, 95% CI-1.5 to 2.0 mm). There was no significant difference between the median gestational age estimate based on crown-rump length and that based on the women's last menstrual period. CONCLUSION: In antenatal screening for Down's syndrome the routine use of an ultrasound biparietal diameter or crown-rump length measurement to estimate gestational age will not adversely affect the detection rate. To avoid differences in gestational age estimates using the last menstrual period and the biparietal diameter influencing screening performance, separate medians should be derived for each serum marker using the two methods of estimating gestational age. The appropriate set of medians can then be used to calculate the multiple of the median value for each woman screened depending on the method used to estimate her gestational age.

Case-Control Studies↗
PubMed1993

Cigarette smoking and levels of maternal serum alpha-fetoprotein, unconjugated estriol, and hCG: impact on Down syndrome screening.

OBJECTIVE: To investigate the association between maternal cigarette smoking and serum levels of alpha-fetoprotein (AFP), unconjugated estriol (uE3), and hCG and to determine whether it is appropriate to take smoking status into account when screening for fetal Down syndrome. METHODS: Smoking information was obtained from 23,668 pregnant women at the time of routine screening for fetal Down syndrome. Serum levels of AFP, uE3, and hCG were stratified by smoking status and compared. Individual risks for fetal Down syndrome were analyzed both before and after adjusting the hCG levels for the effect of smoking. The prevalence of Down syndrome in the study population was calculated for both smokers and non-smokers. RESULTS: The average AFP, uE3, and hCG levels in women who smoked cigarettes were 3% greater (95% confidence interval [CI] 2-4%), 3% less (95% CI 2-4%), and 23% less (95% CI 22-24%), respectively, compared with levels in non-smokers. At comparable maternal ages, women who smoked cigarettes were identified as being at high risk for fetal Down syndrome 40% less often than non-smokers (4.0 versus 7.1% at a risk level of 1:250). Adjusting hCG levels for smoking status reduced the overall false-positive rate from 6.4 to 6.1% (using a term risk cutoff level of 1:250). The predicted effect on detection was small (a 0.7% increase). The prevalence of Down syndrome was lower among smokers, but the difference was not statistically significant (odds ratio 0.51, 95% CI 0.15-1.5). CONCLUSIONS: Adjusting the serum markers used for Down syndrome screening for the effect of maternal smoking has a small effect on overall screening performance. Given the uncertainty over whether there is a lower birth prevalence among women who smoke cigarettes, such adjustment is not currently justified.

Adult↗