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     

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.     

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.     

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.     

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.     

Taking account of gender in the clinical assessment interview.

The impact of gender-related factors on clinical assessment is addressed. Studies reviewed show a neglect of gender in standard assessment, leading to less powerful findings in the assessment process. Various facets of gender in clinical assessment examined include the meaning of gender for both clinician and client, the demand characteristics of gender and gender roles, and intrusion of gendered (i.e., gender-related) stereotypes into clinical assessment and diagnosis. The use of gender role analysis in clinical assessment is described, as are strategies for psychologists to become more sensitive to gender issues and more capable of integrating them into the clinical assessment process. Steps by which to become a more gender-aware assessor are outlined. Inclusion of gender issues in standard training in clinical assessment for psychologists is supported. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Olfactory function in young adolescents with Down's syndrome

Decreased ability to smell is present in adults with Down's syndrome, many of whom are known to have brain pathology analogous to that seen in Alzheimer's disease. Because olfactory loss is well documented in Alzheimer's disease, the question arises whether young adolescents with Down's syndrome, who have no clear Alzheimer's disease-like neuropathology, also exhibit olfactory dysfunction. To consider this issue, standardised tests of odour discrimination and identification were administered to 20 young adolescents with Down's syndrome (mean age (SD) 13.89 (1.98) years) and their test scores were compared with 20 mentally retarded and 20 non-mentally retarded control subjects matched to the patients with Down's syndrome on the basis of cognitive ability. No significant differences in olfactory function were found among the three study groups. These findings, along with those from studies of olfactory function in older patients with Down's syndrome, suggest that Down's syndrome related olfactory dysfunction occurs only at ages when Alzheimer's disease-like pathology is present.     

Association of Down's syndrome and testicular cancer

PURPOSE: We present additional clinical evidence for the suspected association of Down's syndrome and testicular germ cell tumors. MATERIALS AND METHODS: Four cases of Down's syndrome and testicular cancer are reported. The literature was reviewed for previous cases and analysis regarding common features. RESULTS: The 4 patients were 29 to 35 years old and had clinical stage I seminoma of the testis. Two patients received prophylactic abdominal radiotherapy, 1 is being followed and 1 received adjuvant carboplatin treatment. There was no relapse at followup of 1 to 8 years. One patient also had contralateral cryptorchidism. A total of 16 cases with the association of Down's syndrome and testicular germ cell cancer was documented previously. CONCLUSIONS: Evidence for the suspected association of Down's syndrome and testicular cancer is now accumulating. Etiologically it is suspected that, along with genetically determined malformations in many other organs in trisomy 21, the gonads also undergo maldevelopment, thus creating the conditions for step 1 of germ cell tumor oncogenesis in utero. Physicians caring for patients with Down's syndrome should be aware of the possible association with testicular neoplasms.