Multiple fetal anomalies associated with subtle subtelomeric chromosomal rearrangements.

We report two cases of multiple fetal anomalies detected by prenatal ultrasound and associated with subtle subtelomeric chromosomal rearrangements. The first case presented at 25 weeks of gestation with an enlarged cisterna magna and ventriculomegaly. Karyotyping of amniocytes showed a subtle terminal abnormality of chromosome 6q. Thereafter, screening of all unique chromosomal subtelomeric regions using a panel of telomere-specific, fluorescence in situ hybridization (FISH) probes revealed an unbalanced reciprocal translocation between 6q and 17p [46,XX.ish der(6)t(6;17)(q25.3;p13)(TelVysion6q-;TelVysion17p+)]. The second case presented at 25 weeks of gestation with tetralogy of Fallot and at 34 weeks of gestation had additional ultrasound findings of an arachnoid cyst and intrauterine growth restriction. Postnatal karyotyping of peripheral blood was performed and appeared normal. However, a cryptic deletion of the subtelomeric region of the long arm of chromosome 14 was identified when the infant's blood sample was used as a control for an oncology FISH probe. Thereafter, screening of all unique chromosomal subtelomeric regions using a panel of telomere-specific FISH probes revealed an unbalanced reciprocal translocation of chromosomes 14q and 20p [46,XY.ish der(14)t(14;20)(q32.3;p13)(IGH-, D14S308-,TelVysion20p+)mat]. These two cases add to a growing number of reports of cryptic subtelomeric chromosomal rearrangements associated with congenital anomalies. This is the first report of multiple, simultaneous FISH screening of the subtelomeric regions in amniotic fluid and has demonstrated the technical feasibility of this technique in the prenatal period.

Survey of psychological health in women with infertility.

The aims of this study were to assess mental well-being in women undergoing investigation and initial management of infertility and to determine any specific factors, such as the duration or type of infertility, that might be associated with an increased risk of psychological morbidity. A postal survey was sent to 1080 women with infertility attending gynecology outpatient departments in 12 Scottish centres. The survey included the Twelve-Item General Health Questionnaire (GHQ-12) and three multi-item scales from the Short Form Health Survey Questionnaire (SF-36). The response rate was 47.4% (512/1080) of which 507 completed the GHQ-12. Of the 507 GHQ-12 responders, 32.5% had a GHQ-12 score of > or = 8/12 suggesting they were at risk of clinically significant psychological disturbance. There were no significant associations between GHQ-12 scores and duration of infertility, the presence of existing children, or the cause of infertility. GHQ-12 scores significantly increased with the number of clinic attendances and decreased as the patient's age increased. Responders scored significantly lower on all aspects of the selected SF-36 questions as compared to published population data, suggesting poorer mental health. These standardized psychological instruments suggest that approximately 32% of women in the early stages of infertility management may be at risk of developing clinically relevant mental health problems. Psychological aspects of infertility should be addressed as part of a more holistic approach to management of these patients.

Isolated sonographic markers for detection of fetal Down syndrome in the second trimester of pregnancy.

OBJECTIVE: To determine whether sonographic "markers" are associated with fetal Down syndrome during the second trimester and to estimate the degree of risk of individual markers using likelihood ratios. METHODS: Second-trimester (14-20 weeks) sonographic findings in 186 fetuses with trisomy 21 were compared with a control group of 8728 consecutive control fetuses. Six markers were evaluated: nuchal thickening, hyperechoic bowel, shortened femur, shortened humerus, echogenic intracardiac focus, and renal pyelectasis. RESULTS: Major or structural abnormalities were observed in 31 fetuses with trisomy 21 (16.7%) and 53 control fetuses (0.6%) (P< .001). Some type of sonographic finding (major abnormality, minor marker, or both) was observed in 68.8% of fetuses with trisomy 21 compared with 13.6% of control fetuses (P < .001). An isolated minor or "soft" marker was the only sonographic finding in 42 (22.6%) of 186 fetuses with trisomy 21 compared with 987 (11.3%) of 8728 control fetuses (P < .001). Nuchal thickening (P < .001; likelihood ratio, 11) and hyperechoic bowel (P < .001; likelihood ratio, 6.7) showed the strongest association with trisomy 21 as isolated markers, followed by shortened humerus (likelihood ratio, 5.1), echogenic intracardiac focus (likelihood ratio, 1.8), shortened femur (likelihood ratio, 1.5), and pyelectasis (likelihood ratio, 1.5). Echogenic intracardiac focus was the single most common isolated marker in both affected fetuses (7.1%) and control fetuses (3.9%) but carried a low risk (P= .046; likelihood ratio, 1.8). CONCLUSIONS: A single soft marker is commonly encountered during the second trimester among fetuses with trisomy 21. The risk of fetal Down syndrome, reflected by likelihood ratios, was determined for 6 individual markers. This information can be combined with the a priori risk to estimate the individual patient risk for fetal Down syndrome.

Sonographic screening for fetal aneuploidy: first trimester.

OBJECTIVES: Screening for fetal aneuploidy is now possible during the first trimester using sonographic and biochemical markers. The aim of this review was to summarize the efficacy and use of nuchal translucency in screening for fetal aneuploidy, especially fetal Down syndrome, and other anomalies. METHODS: We reviewed available literature regarding first-trimester screening. This includes more than 16 studies of nuchal translucency as a marker for fetal aneuploidy published since 1995. RESULTS: Although early studies showed wide variation in detection of fetal Down syndrome when using nuchal translucency, more recent studies showed sensitivities of approximately 70% to 80%, for a 5% false-positive rate. Increased nuchal translucency has also been found to be a marker for other aneuploidies, including trisomy 18, trisomy 13, and Turner syndrome. Maternal serum biochemical screening can be used as a test for aneuploidy during the first trimester The 2 maternal serum markers that appear to be most useful in the late first trimester are the free beta subunit of human chorionic gonadotropin and pregnancy-associated plasma protein A. Together with maternal age, these markers yield a detection rate for trisomy 21 of approximately 60%, for a 5% false-positive rate. Because sonographic and biochemical markers appear to be largely independent, their combined risk results in improved detection rates compared with either method alone. As a result, the combination of nuchal translucency, biochemical markers, and maternal age has achieved a detection rate of approximately 85%, for a 5% false-positive level for detection of trisomy 21. A newly proposed "integrated" approach using a panel of first- and second-trimester markers suggests that further improvement in the screening performance is possible. A number of questions regarding first-trimester screening remain. We address some of these questions: is first-trimester screening more effective than second-trimester screening? How to account for intrauterine lethality? Is earlier diagnosis important, and will it be accepted by patients? Is first-trimester screening cost-effective? How should first-trimester screening be interpreted with second-trimester tests? CONCLUSIONS: Despite encouraging data and general enthusiasm for first-trimester screening for fetal Down syndrome and other aneuploidies, a number of questions remain about its implementation in the United States. Multicenter studies currently under way should help answer some of these questions.

Sonographic markers of fetal trisomies: second trimester.

OBJECTIVE: Second-trimester sonographic findings of fetal trisomy may include structural abnormalities or sonographic markers of fetal aneuploidy. Unlike structural anomalies, sonographic markers of fetal aneuploidy are insignificant by themselves with regard to outcome, are nonspecific--most frequently seen in normal fetuses, and are often transient. Our objective was to review the second-trimester sonographic findings of the major trisomic conditions, trisomies 13, 18, and 21. METHODS: We reviewed a number of the most commonly accepted markers, including nuchal thickening, hyperechoic bowel, echogenic intracardiac focus, renal pyelectasis, shortened extremities, mild cerebral ventricular dilatation, and choroid plexus cysts. Markers associated with trisomy 21 were emphasized. RESULTS: The sensitivity of sonography for detection of fetal trisomic conditions varies with the type of chromosome abnormality, gestational age at the time of sonography, reasons for referral, criteria for positive sonographic findings, and the quality of the sonography. As an estimate, 1 or more sonographic findings can be identified in approximately 90% of fetuses with trisomy 13, 80% of fetuses with trisomy 18, and 50% to 70% of fetuses with trisomy 21 (Down syndrome). CONCLUSIONS: The presence or absence of sonographic markers can substantially modify the risk of fetal Down syndrome and is the basis of the so-called genetic sonogram. Because maternal biochemical and sonographic markers are largely independent, combined risk estimates will result in even higher detection rates than either alone.

Echogenic intracardiac focus in 2nd-trimester fetuses with trisomy 21: usefulness as a US marker.

PURPOSE: To determine whether there is a relationship between the presence of an echogenic intracardiac focus in 2nd-trimester fetuses and trisomy 21 (Down syndrome). MATERIALS AND METHODS: A complete genetic ultrasonographic (US) scan was obtained in 3,303 consecutive fetuses with an estimated gestational age of 14.0-24.0 weeks (mean +/- SD, 17.1 weeks +/- 1.75). US was performed in a prospective fashion without any knowledge of karyotype and included assessment of any potential echogenic intracardiac focus (ie, calcified papillary muscle). Karyotypes were obtained in all fetuses. Maternal ages ranged from 13.0 to 47.4 years (mean, 35.1 years +/- 5.1). The prevalence of Down syndrome in this population was 1.6% (53 of 3,303 fetuses). RESULTS: An echogenic intracardiac focus was seen in 147 of the 3,192 karyotypically normal fetuses (4.6%) and 16 of the 53 fetuses with trisomy 21 (30%). The positive predictive value (PPV) of an echogenic intracardiac focus in this high-risk population was 9.8%; sensitivity, 30%; specificity, 95%; likelihood ratio, 6.6; and relative risk (RR), 8.2 (P <.001). For a sonographically isolated echogenic intracardiac focus, the PPV was 3.7%; sensitivity, 19%; specificity, 95%; likelihood ratio, 4.2; and RR, 4.8 (P =.002). CONCLUSION: A sonographically isolated echogenic intracardiac focus (no other anomalies or markers noted on a complete genetic sonogram) was associated in our high-risk population with a 4.8-fold (95% CI: 1.8, 12.5) increase in RR for trisomy 21 (P =.002).

The "genetic sonogram": comparison of the index scoring system with the age-adjusted US risk assessment.

PURPOSE: To compare two ultrasonographic (US) methods for prenatal detection of fetal Down syndrome. MATERIALS AND METHODS: Genetic amniocentesis was successfully performed in 3,303 consecutive women with high-risk pregnancies (mean gestational age, 17.1 weeks). All patients underwent a complete "genetic US" examination prospectively. Risk was assessed by using (a) various modifications of the index scoring system (ISS) and (b) the age-adjusted US risk assessment (AAURA). RESULTS: The prevalence of Down syndrome in this population was 1.6% (53 of 3,303). By using a threshold of at least 2 points to detect trisomy 21, the best ISS had a sensitivity of 45.3%, false-positive rate of 4.9%, likelihood ratio of 9.3, and positive predictive value in the high-risk population in this study of 13.3%. Lowering the threshold to 1 point increased the sensitivity to 60.4% but increased the false-positive rate to 15.8%. Adding points for age increased the sensitivity to 67.9% but increased the false-positive rate to 24.3%. Results of using AAURA to detect trisomy 21 were nearly identical, with a sensitivity of 43.4% and false-positive rate of 4.9% at a 1 in 36 risk threshold and a sensitivity of 69.8% and false-positive rate of 26.1% at a 1 in 200 threshold. Trisomies 18 and 13 were detected with sensitivities of 80.0% and 100.0%, respectively, with either system. CONCLUSION: The modified ISS and AAURA are equivalent in screening for Down syndrome, with detection of approximately half of all trisomy 21 fetuses at a 5% false-positive rate.

Sonographic markers of fetal aneuploidy.

A variety of ultrasound findings can be identified in fetuses with fetal aneuploidy. Typical findings vary with both the chromosome abnormality and gestational age at time of the ultrasound examination. Increased NT is the primary marker during the first trimester, whereas a variety of markers may be seen during the second trimester. The presence of ultrasound markers increases the risk for fetal aneuploidy, whereas a normal ultrasound reduces the risk. Optimal risk assessment includes consideration of other risk factors including maternal age, family history, and biochemical markers. It is expected that combined risks, incorporating ultrasound findings and biochemistry, will be available in the near future. How first-trimester screening is integrated with second-trimester screening remains to be determined.

Early diagnosis of major cardiac defects in chromosomally normal fetuses with increased nuchal translucency.

OBJECTIVE: To determine the value of early ultrasound examination for prenatal diagnosis of cardiac defects in chromosomally normal fetuses with increased nuchal translucency thickness at 10-14 weeks of gestation. DESIGN: Prospective audit. SETTING: Fetal Medicine Centre. METHODS: Specialist fetal echocardiography was carried out in 398 chromosomally normal fetuses with a nuchal translucency measurement above the 99th centile (> or = 3.5 mm). In the first 75 pregnancies the cardiac scan was carried out at 17-22 weeks and the next 323 cases had one scan at 13-17 weeks and another at 20-22 weeks. Pregnancy outcome was obtained in all of the cases. RESULTS: Major cardiac defects were present in 29 (7.3% of 398) cases and in 28 of these the diagnosis was made by antenatal echocardiography. In 27 of the 29 fetuses with major cardiac defects echocardiography was carried out at 13-17 weeks and an abnormality was suspected in 24 of the cases (88%). CONCLUSIONS: Increased nuchal translucency in chromosomally normal fetuses is associated with an increased prevalence of major cardiac defects and, as such, is an indication for specialist fetal echocardiography. Most of the cardiac abnormalities are detectable on antenatal fetal echocardiography and many can be excluded by early scanning.

Patient satisfaction with the management of infertility.

The objective of this study was to assess patient satisfaction with the investigation and initial management of infertility. A postal questionnaire survey was carried out of 1366 women attending outpatient clinics for the investigation and initial management of infertility at 12 hospitals throughout Scotland. The response rate to the questionnaire was 59% (806/1366). Overall, 87% of responders were satisfied or very satisfied with their care but a number of deficiencies were identified. Thirty-nine per cent had never been asked to bring their partner to the clinic and 86% felt they had not been given enough help with the emotional aspects of infertility. Forty-seven per cent felt they were not given a clear plan for the future and 23% of those who had been given drug treatments reported receiving little or no information about the treatment or possible side-effects. Overall, only a third had been given any written information and 78% expressed a wish for more written information. Women ranked 'the information and explanation given' and the 'attitude of the doctor at the clinic' highly in comparison to other aspects of their care, including 'help with the emotional aspects of infertility'. In general women were satisfied with their care but improvements may be made by giving more explanation and written information and by adopting a more couple-centred approach. Where resources allow, clinics should take steps to address the emotional aspects of infertility.

Laboratory techniques for semen analysis: a Scottish survey.

OBJECTIVE: To survey the techniques used by Scottish laboratories to undertake semen analysis in the context of the investigation of infertility. DESIGN: A telephone survey. SETTING/SUBJECTS: Laboratories in Scotland performing semen analysis. RESULTS: Thirty-one laboratories reported performing semen analysis for infertility. There was a lack of consistency in the instructions given to patients in several areas, including the period of abstinence prior to producing the specimen and the delivery of the specimen to the laboratory within an appropriate time after ejaculation. Only 19% of laboratories reported using a positive displacement pipette in the dilution of semen and only 26% used phase contrast microscopy for routine semen analysis. The minimum normal values quoted by laboratories for sperm concentration ranged from 20 x 10(6)/ml to greater than 50 x 10(6)/ml. The normal values quoted for sperm morphology ranged from at least 30% normal forms to at least 88% normal forms. Only 13% of laboratories participated in any form of internal or external quality control for semen analysis. CONCLUSIONS: Semen analysis is fundamental to the clinical work up of the infertile couple but, unlike most other laboratory investigations, it is not a standardised test in Scotland. Factors which are known to influence the results such as the advice given to patients about collecting specimens and the methods and equipment used by technicians vary widely. There is not even a consensus on the normal values quoted. This has implications for clinical decisions based on semen analysis and for future accreditation of laboratories.

A survey of infertility practices in primary care in Scotland.

An 83% response rate was obtained to a postal questionnaire survey of general practitioners (GPs) carried out as part of a national infertility audit in Scotland. This provided information about how GPs are managing infertility and their opinions on 12 suggested criteria for good practice in a primary care setting.