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     

The value of screening for Down's syndrome in a socioeconomically deprived area with a high ethnic population

OBJECTIVE: To assess the utility of biochemical antenatal screening for Down's syndrome in a socioeconomically deprived area with a high proportion of Asian women from the Indian Subcontinent. DESIGN: Audit of Down's syndrome biochemical screening service over a four-year period. SETTING: Teaching hospital and community antenatal clinic in inner city Birmingham. POPULATION: Women booked between October 1992 and December 1996. METHODS: Blood for screening was collected between 14 and 21 weeks gestation, alpha-fetoprotein and intact human chorionic gonadotrophin were measured in serum and the risk of Down's syndrome was calculated. MAIN OUTCOME MEASURES: Uptakes of screening and amniocentesis, screen positive rate, odds of being affected given a positive result, miscarriages associated with amniocentesis offered following a high risk result, detection rate, number of Down's cases prevented and a cost analysis. Outcome measures were compared between Asians and Caucasians. RESULTS: Overall 11,974 women (71%) accepted serum screening. The screen positive rate was 8.3% in Asians and 5.0% in Caucasians. The uptake of amniocentesis in women following a high risk result was 54% overall (35% Asian, 67% Caucasian). Nineteen cases of Down's syndrome were identified, of which 13 occurred in women who opted for biochemical screening. The detection rate of the biochemical screening programme was 85% (11/13). Of these 11 cases, six (none of whom were Asian) elected to have an amniocentesis, of whom four thereafter had a termination. CONCLUSION: In this study the public health benefits of screening for Down's syndrome in a socioeconomically deprived area with a high Asian population, were small.     

Taking account of vaginal bleeding in screening for Down's syndrome

OBJECTIVE: To derive a method for revising the risk of Down's syndrome in maternal serum marker screening when there is vaginal bleeding. The effect on screening performance of routinely allowing for the presence or absence of bleeding in all women is also assessed. DESIGN: Overview of published studies on the rate of reported vaginal bleeding in pregnancies with Down's syndrome, on the rate according to maternal age and on the association of bleeding with alpha-fetoprotein (AFP) level. The publications are supplemented with data on unconjugated oestriol (uE3), human chorionic gonadotrophin (hCG) and AFP levels in a consecutive series of screened women. SETTING: Routine Down's syndrome screening tests carried out on women having antenatal care at the St James's University Hospital, Leeds. SUBJECTS: Eight hundred and nine screened women. RESULTS: In five studies the rate of vaginal bleeding in Down's syndrome pregnancies was 1.7 times that in unaffected pregnancies on average. In three studies, the vaginal bleeding rate increased proportionally by 2.2% on average for each year of maternal age. Three studies and our own data were consistent with a 10% increase in the mean AFP level associated with vaginal bleeding, but it did not appear to materially alter uE3 and hCG levels or the standard deviations and correlation coefficients for any of the three analytes. An individual woman's risk was calculated by multiplying her age-specific odds of Down's syndrome by two likelihood ratios, one relating to the vaginal bleeding itself and one from the marker levels. Routine allowance for the presence or absence of vaginal bleeding was estimated to increase the detection rate by less than 1%. CONCLUSION: Our method is of clinical value in revising the risk when there is concern that vaginal bleeding might be responsible for a negative maternal serum Down's syndrome screening result. A policy of routinely incorporating information on vaginal bleeding in risk estimation for all women would have too small an effect on overall screening performance to recommend it.     

Effect of routine screening for Down's syndrome on the significance of isolated fetal hydronephrosis

OBJECTIVE: To determine the risk of Down's syndrome in fetuses with isolated hydronephrosis at 18-23 weeks in an unselected general population after routine screening for Down's syndrome, using first trimester nuchal translucency measurement and second trimester maternal serum biochemistry. POPULATION: All pregnant women undergoing a routine 18-23 week ultrasound scan, from a population who had been offered screening for Down's syndrome. SETTING: A district general hospital serving a low risk obstetric population. METHODS: Prospective study of all routine 18-23 weeks ultrasound scans. The prevalence of isolated hydronephrosis and Down's syndrome was determined and the relative risk for Down's syndrome was calculated for different ultrasound findings. RESULTS: 10,971 women were scanned at 18-23 weeks during the study period. Down's syndrome was diagnosed in 14 of 20 cases before this stage using first trimester nuchal translucency measurement and second trimester maternal serum biochemistry. Isolated fetal hydronephrosis was diagnosed in 423 pregnancies (3.9%); none of these pregnancies were affected by Down's syndrome. The relative risk for Down's syndrome was 0.18 (95% CI 0.06-0.53) for women with a normal scan (n = 9983). When multiple ultrasound markers were found (n = 565), the relative risk for Down's syndrome was 2.00 (95% CI 0.18-22.10) and 9.00 (95% CI 1.14-71.30) for all other aneuploidies. CONCLUSION: The finding of isolated fetal hydronephrosis does not significantly increase the age-related risk for Down's syndrome. The presence of multiple ultrasound markers is associated with an increased risk of aneuploidies other than Down's syndiome. These findings are explained by the reduced prevalence of Down's syndrome as a result of prior screening and diagnosis of this condition.     

Folliculitis in Down's syndrome

Twenty-two male and 20 female adults with Down's syndrome were examined. Ten of the men and two of the women had a follicular rash consistent with Malassezia folliculitis. Oral itraconazole treatment produced a significant improvement in the rash, accompanied by a decrease in the skin Malassezia count. Clinical relapse occurred when therapy was discontinued, and was accompanied by return of the Malassezia yeasts.     

Rapid prenatal diagnosis of Down's syndrome in the first trimester of pregnancy by fluorescence in situ hybridization

OBJECTIVE: To assess whether fluorescence in situ hybridization (FISH) with chromosome 21, specific DNA probe is applicable as a prenatal diagnostic tool for Down's syndrome. METHOD: We used FISH with chromosome 21 specific probe on 30 uncultured chorionic villi cell samples to detect the Down's fetus, and we also performed the conventional chromosome analysis of chorion cells from parallel samples. RESULTS: In samples with disomic karyotype, an average of 1 percent (0-5 percent) of the nuclei had three hybridization signals. By contrast, in the samples of trisomy 21 fetus, an average of 86 percent (78-91 percent) of the nuclei displayed three signals. CONCLUSION: FISH can provide a rapid and accurate method for the first trimester prenatal diagnosis of Down's syndrome.     

Effect of ethnic media on cervical cancer screening rates

We report the case of an immunocompetent patient who has been the subject of 39 episodes of recurrent pneumococcal meningitis over a 20 year period. The recurrences of bacterial meningitis due to cerebrospinal fluid leakage and the presence of chronic sinusitis were not influenced by the surgical repair of a fistula and the repeated surgical draining interventions on suppurating chronic sinusital foci. Phenoxymethylpenicillin treatment reduced the number of recurrences and the combination of pneumococcal vaccine and penicillin prophylaxis allowed a 5 year period free of any recurrences.     

Economic evaluation of prenatal screening for Down syndrome in the U.S.A

Maternal serum screening for Down syndrome involves biochemical tests such as alpha-fetoprotein (alpha FP), human chorionic gonadotrophin (hCG) and unconjugated oestriol (uE3), either alone or in combination, that have variable detection and false-positive rates. Choosing a screening protocol requires a trade-off between a desired detection rate and an acceptable false-positive rate. Selecting a screening protocol that maximizes the net benefit to society provides one approach. We have developed a general formula for calculating the per case net social benefit of a screening test and have applied it to United States data. The maximum net benefit associated with each of the various screening options currently available is estimated and the model is further applied to determine the conditions under which the addition of a new marker to an existing protocol can be justified. For each test, or combination of tests, optimal net benefits occur at different detection and false-positive rates. Net benefits are strongly and positively dependent on maternal age; high net benefits are associated with older patients and low, or even negative, net benefits with younger patients. Also, net benefits are affected by the term risk cut-off rate. For triple testing, the 1:351 Down syndrome term risk cut-off appears to provide a higher net benefit than that obtained with 1:250 or 1:300. The optimization of societal net benefit provides a powerful approach to evaluating screening strategies, but the policies used must also consider individuals' freedom in decision making at each step of the prenatal diagnosis pathway.     

Routine prenatal screening for HIV in a low-prevalence setting

BACKGROUND: The objectives of this study were to assess the effect of British Columbia's June 1994 guidelines for prenatal HIV screening on the rate of maternal-fetal HIV transmission and to estimate the cost-effectiveness of such screening. METHODS: The authors conducted a retrospective review of pregnancy and delivery statistics, HIV screening practices, laboratory testing volume, prenatal and labour management decisions of HIV-positive women, maternal-fetal transmission rates and associated costs. RESULTS: Over 1995 and 1996, 135,681 women were pregnant and 92,645 carried to term. The rate of HIV testing increased from 55% to 76% of pregnancies on chart review at one hospital between November 1995 and November 1996. On the basis of seroprevalence studies, an estimated 50.2 pregnancies and 34.3 (95% confidence interval 17.6 to 51.0) live births to HIV-positive women were expected. Of 42 identified mother-infant pairs with an estimated date of delivery during 1995 or 1996, 25 were known only through screening. Of these 25 cases, there were 10 terminations, 1 spontaneous abortion and 14 cases in which the woman elected to carry the pregnancy to term with antiretroviral therapy. There was one stillbirth. One instance of maternal-fetal HIV transmission occurred among the 13 live births. The net savings attributable to prevented infections among babies carried to term were $165,586, with a saving per prevented case of $75,266. INTERPRETATION: A routine offer of pregnancy screening for HIV in a low-prevalence setting reduces the rate of maternal-fetal HIV transmission and may rival other widely accepted health care expenditures in terms of cost-effectiveness.     

First trimester screening for Down's syndrome using maternal serum PAPP-A and free beta-hCG in combination with fetal nuchal translucency thickness

The aim of this study was to evaluate the potential effectiveness of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG in combination with nuchal translucency thickness in first trimester screening for Down's syndrome. Maternal serum levels of PAPP-A and free beta-hCG were assayed in stored sera from 32 Down's syndrome and 200 unaffected pregnancies. Fetal nuchal translucency was measured by ultrasound at the time of blood sampling. Screening of Down's syndrome using a combination of maternal age, PAPP-A, free beta-hCG and nuchal translucency would achieve a detection rate of 75.8% for a false positive rate of 5%.     

Hyperthyroidism in a girl with Down's syndrome

We report an adolescent girl with Down's syndrome, who presented with hyperthyroidism. Autoimmune thyroid disorders can occur in children with Down's syndrome, hypothyroidism developing more frequently. Hyperthyroidism can also be associated with Down's syndrome, and should not be missed.     

Screening of maternal serum for fetal Down's syndrome in the first trimester

BACKGROUND: Screening of maternal serum to identify fetuses with Down's syndrome is now routinely offered during the second trimester of pregnancy. Prenatal screening by means of serum assays or ultrasonographic measurements, either alone or in combination, may also be possible in the first trimester. METHODS: We measured serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin (hCG), the free beta subunit of hCG, and pregnancy-associated protein A in 4412 women (82 percent of whom were 35 years of age or older) who came to 16 prenatal diagnostic centers for chorionic-villus sampling or early amniocentesis at 9 to 15 weeks of gestation. Ultrasound measurements of fetal nuchal translucency were also reported. Fetal chromosomal analysis was performed in all pregnancies. Altogether, there were 61 fetuses with Down's syndrome. RESULTS: A total of 48 pregnancies affected by Down's syndrome and 3169 unaffected pregnancies were identified before 14 weeks of gestation; the rates of detection of Down's syndrome for the five serum markers were as follows: 17 percent for alpha-fetoprotein, 4 percent for unconjugated estriol, 29 percent for hCG, 25 percent for the free beta subunit of hCG, and 42 percent for pregnancy-associated protein A, at false positive rates of 5 percent. The results of the measurements of serum hCG and its free beta subunit were highly correlated. When used in combination with the serum concentration of pregnancy-associated protein A and maternal age, the detection rate was 63 percent for hCG (95 percent confidence interval, 47 to 76 percent) and 60 percent for its free beta subunit (95 percent confidence interval, 45 to 74 percent). Measurements of nuchal translucency varied considerably between centers and could not be reliably incorporated into our calculations. CONCLUSIONS: Screening for Down's syndrome in the first trimester is feasible, with use of measurements of pregnancy-associated protein A and either hCG or its free beta subunit in maternal serum.