The importance of a genetic evaluation of prospective ovum donors: a study of family history and genetic carrier testing.

OBJECTIVE: To determine the percentage of potential ovum donors who have an increased risk for fetal harm. STUDY DESIGN: Couples using an ovum donor to conceive a pregnancy are expecting to select someone who poses a low genetic risk to their offspring. Currently, most genetic carrier screening of these donors is performed at the discretion of the fertility center. This investigation involves a review of family history and genetic carrier test results of oocyte donor candidates. RESULTS: A total of 210 (22.1%) of 950 potential oocyte donors had at least one fetal risk factor based on family history. Of 244 prospective donors who had genetic testing, 15 (6.1%) were found to be carriers of hereditary diseases that could pose an increased risk to a fetus. CONCLUSION: A genetic assessment is a critical step in the evaluation of prospective oocyte donors, because almost one quarter of donors had a family history of a disease that could pose an increased fetal risk. Disclosure of ovum donor carrier status and, when applicable, testing of partners is required before accepting a potential ovum donor in an infertility program.

Maternal reactions to two-dimensional compared to three-dimensional foetal ultrasonography.

Our objective was to quantitatively compare maternal reactions to viewing a three-dimensional (3D) ultrasound image of the foetal face to a traditional two-dimensional (2D) sonographic image. One hundred and twelve pregnant women were asked to evaluate their excitement, relief, amazement and satisfaction reactions to 2D and 3D ultrasound images of their foetus' face. A weighted kappa Cochran-Armitage trend test, Fisher exact test and generalised estimating equations were used to analyse the data obtained. 3D imaging was found to result in significantly more favourable reactions than 2D imaging of the foetal face. 3D imaging was significantly better than 2D in regard to the clearness of the image, feeling closer to the baby, experiencing amazement and recognising specific facial features. We hypothesised that 3D images might evoke more feelings of fear than 2D, but our analysis found there were no significant differences in this regard. 3D ultrasonography of the foetal face is well received by patients. It has been shown in this study to elicit stronger and more positive maternal reactions regarding excitement, amazement and satisfaction than experienced with 2D ultrasound.

Moderately increased risks of Down's syndrome (1/51-1/270) identified on first trimester sequential screening: what do patients do with this information?

OBJECTIVE: To document patient decisions after being informed of a first trimester sequential screen Down's syndrome risk between 1/51 and 1/270. SETTING: A database analysis of sequential screen results for patients seen in the Philadelphia, PA (USA) area between January 2006 and March 2008 was examined. METHODS: All patients with first trimester sequential screen Down's syndrome risks in the 1/51-1/270 range were identified. Patient decisions regarding invasive testing (prior to completing the second trimester stage of the sequential screen), completion of the second trimester blood draw or no additional testing were tabulated. RESULTS: A total of 10,850 patients underwent first trimester sequential screening during this interval. Five hundred and fifty-seven patients (5.1%) met the study inclusion criteria and had risks between 1/51 and 1/270. Ninety-three percent of these patients completed the sequential screening process before making any decisions regarding invasive testing. Four percent did not elect an invasive prenatal diagnosis procedure, but also did not complete the second trimester sequential screening blood draw and only 3.2% elected an invasive procedure based on their first trimester risk without completing the second trimester blood draw. Five women (0.9%) with low risks after the second stage screen chose to have an amniocentesis. CONCLUSION: The vast majority (97%) of patients in the moderately increased Down's syndrome risk range (1/51-1/270) following first trimester sequential screening did not pursue an invasive procedure based on their first trimester sequential screen risk. Using a > or = 1/50 risk cut-off in the first trimester is an effective screening policy for sequential screening.

Technical standards and guidelines: prenatal screening for Down syndrome that includes first-trimester biochemistry and/or ultrasound measurements.

This statement is intended to augment the current general ACMG Standards and Guidelines for Clinical Genetics Laboratories and to address guidelines specific to first-trimester screening for Down syndrome. The aim is to provide the laboratory the necessary information to ensure accurate and reliable Down syndrome screening results given a screening protocol (e.g., combined first trimester and integrated testing). Information about various test combinations and their expected performance are provided, but other issues such as availability of reagents, patient interest in early test results, access to open neural tube defect screening, and availability of chorionic villus sampling are all contextual factors in deciding which screening protocol(s) will be selected by individual health care providers. Individual laboratories are responsible for meeting the quality assurance standards described by the Clinical Laboratory Improvement Act, the College of American Pathologists, and other regulatory agencies, with respect to appropriate sample documentation, assay validation, general proficiency, and quality control measures. These guidelines address first-trimester screening that includes ultrasound measurement and interpretation of nuchal translucency thickness and protocols that combine markers from both the first and second trimesters. Laboratories can use their professional judgment to make modification or additions.

Características y perspectivas de las familias que están en espera de adoptar a un niño con síndrome de Down / No disponible

La adopción de niños con necesidades especiales es una experiencia relativamente nueva. En los 1950s, rara vez se consideró la adopción como una opción si el niño tenía retraso mental. En los ochenta, sin embargo, la tendencia había cambiado en relación con la adopción de niños con necesidades especiales. De acuerdo con el Comité Nacional de Adopción en 1985, el 27,6% de todas las adopciones de niños sin relación familiar en USA fue para niños con necesidades especiales. Y a mediados de los noventa la cifra aumentó al 48,5% para niños con discapacidad. Desde que se publicaron los primeros estudios a finales de los 60 sobre la posibilidad de que la amniocentesis permitía detectar las aberraciones cromosómicas, incluida la trisomía 21, cientos de miles de mujeres han utilizado esta técnica y a muchas se les ha informado que su feto tenía síndrome de Down. Con frecuencia se aconseja a los matrimonios que lo tienen dos opciones: continuar o interrumpir el embarazo. Una tercera es la de continuar el embarazo y dar el niño para adopción después del nacimiento. Hasta hace poco, no se hablaba tradicionalmente de la adopción porque muchos profesionales no eran conscientes de que existían familias que deseaban adoptar niños con necesidades especiales. Aunque existe mayor conocimiento, muchos ginecólogos no están todavía familiarizados con esta posibilidad. Se dispone de poca información sobre la naturaleza de las familias que están interesadas en la adopción de niños con síndrome de Down. Un estudio francés de 1988 mostró que el 19% de los bebés con síndrome de Down nacidos en las regiones de París y Marsella entre 1981 y 1990 fueron ofrecidos en adopción por sus padres biológicos pero sólo la mitad fueron finalmente adoptados. En Inglaterra, una agencia informó a finales de los 90 que en menos de una década había puesto en adopción a 35 niños con síndrome de Down. Los investigadores concluyeron que la adopción de estos niños no sólo era una posibilidad realista sino que en general hay un número suficiente de familias para elegir, de modo que se encuentre una casa adecuada para cada niño. Todos los días algunas familias reciben la noticia de que su feto o su bebé recién nacido tienen síndrome de Down. Estas personas se enfrentan a una decisión difícil. Si la información se recibe durante el embarazo, las opciones consisten en continuarlo y tener el niño, continuarlo y poner al niño en adopción o terminar el embarazo. Si el diagnóstico de síndrome de Down se hace en el momento del nacimiento, sólo quedan las dos primeras opciones. En el momento actual existe muy poca información sobre la disponibilidad y naturaleza de las familias y las personas que están en espera para adoptar niños con síndrome de Down. El objetivo de este estudio es identificar las características de estas familias e individuos y las razones que apoyan su decisión. Además este estudio confía en ofrecer a la comunidad médica una mayor conciencia sobre la posibilidad de que se adopten fetos identificados con el síndrome de Down (AU)

No disponible

The risk of a major trisomy in fetuses with pyelectasis: the impact of an abnormal maternal serum screen or additional sonographic markers.

OBJECTIVE: This study was undertaken to evaluate the contribution of either an abnormal second-trimester maternal serum screen or the presence of additional sonographic markers of aneuploidy to the risk of a major trisomy (13, 18, and 21) in fetuses with pyelectasis. STUDY DESIGN: A retrospective review of a large amniocentesis database was performed. Specimens obtained after the sonographic detection of fetal pyelectasis were eligible for analysis. Age-matched women who underwent amniocentesis solely for maternal anxiety or advanced maternal age served as controls. RESULTS: 760,495 amniocentesis specimens were analyzed. Fetal pyelectasis was detected in 671 cases. Pyelectasis, with either a single or multiple additional sonographic markers, was associated with an 8-fold and 62-fold increase in the prevalence of major trisomies (odds ratio = 7.7, 95% CI = 1.2-32.6, P = 0.02) and (odds ratio = 61.9, 95% CI = 13.2-144.6, P < .001), respectively. Pyelectasis with an abnormal maternal serum screen, with or without additional sonographic markers, was associated with a 32-fold and a 205-fold increase in major trisomies (odds ratio = 32.2, 95% CI = 5.3-94.8, P < .001) and (odds ratio = 205.8, 95% CI = 37.9-427.6, P < .001), respectively. CONCLUSION: In fetuses with pyelectasis, the presence of additional sonographic markers or an abnormal maternal serum screen significantly increases the risk of trisomy 13, 18, and 21.

Characteristics and perspectives of families waiting to adopt a child with Down syndrome.

PURPOSE: The study's purpose was to obtain information on the characteristics and perspectives of families interested in adopting children with Down syndrome. METHODS: A questionnaire-based survey was administered to individuals and families on a waiting list to adopt children with Down syndrome. Information on (1) demographic, (2) family structure, (3) Down syndrome exposure, (4) Down syndrome knowledge, (5) reasons for considering adoption, (6) adoption process, and (7) perspective on raising children with Down syndrome was assessed. RESULTS: From 199 mailed surveys, there were 72 respondents (36.2%) of whom six had previously adopted a child with Down syndrome. Forty-eight percent learned of the possibility of adopting children with Down syndrome through the Internet, whereas only one respondent obtained this information from a medical professional. The primary reasons for considering adoption were that prospective adoptive families were equipped with the necessary resources and had previous positive experiences with individuals who have Down syndrome. CONCLUSIONS: Many families are eager to adopt children with Down syndrome. Interest in this option stems from having resources to care for these children and previous positive experiences with individuals with Down syndrome. Information regarding adoption was rarely obtained from health care providers. When counseling pregnant women diagnosed with a Down syndrome fetus, adoption should be discussed so that all options regarding pregnancy management may be explored.

Prenatal diagnosis of an unexpected interstitial 22q11.2 deletion causing truncus arteriosus and thymic hypoplasia in a ring 22 chromosome derived from a maternally inherited paracentric inversion.

OBJECTIVE: To present the prenatal diagnosis of an interstitial 22q11.2 deletion involving a ring 22 chromosome associated with truncus arteriosus and a hypoplastic thymus. CASE: Following the sonographic diagnosis of a cystic hygroma at 12 weeks of gestation, chromosome analysis revealed a ring 22 chromosome. RESULTS: Ring chromosomes typically result in the deletion of genetic material from the distal long and short arms of the affected chromosome. The presence of an interstitial deletion in a ring chromosome is therefore unusual. FISH analysis revealed an unexpected deletion involving the TUPLE1 gene in the DiGeorge/Velocardiofacial syndrome region in 22q11.2. Maternal chromosome analysis revealed the cause of the apparent interstitial deletion, a paracentric inversion in the long arm of chromosome 22, resulting in the distal long arm of 22q being located adjacent to the centromere and the proximal end being located near the telomere. The fetus was subsequently diagnosed with truncus arteriosus and a hypoplastic thymus, consistent with DiGeorge syndrome. CONCLUSION: The ring chromosome 22 found in the fetus appears to have been derived from a rearrangement of the mother's inverted 22, resulting in ring formation and loss of the end of the distal long arm of the inverted 22, including the TUPLE1 locus, causing DiGeorge syndrome in the fetus. The apparent interstitial deletion was actually a terminal deletion in a maternally inherited rearranged chromosome 22.

Prospective study of 22q11 deletion analysis in fetuses with excess nuchal translucency.

OBJECTIVE: The purpose of this study was to determine the frequency of 22q11 deletions (DiGeorge, velocardiofacial syndromes) in chromosomally normal fetuses with excess nuchal translucency. STUDY DESIGN: We evaluated chorionic villus sampling (CVS) samples submitted with an indication of excess nuchal translucency. If chromosome analysis was normal, permission was obtained to perform 22q11 microdeletion fluorescence in situ hybridization analysis. By Fisher exact test, the null hypothesis that there is no association between excess nuchal translucency and 22q11 deletions was tested. RESULTS: Among 239 CVS samples from fetuses with excess nuchal translucency, 93 (39%) were chromosomally abnormal. Of the remaining 146 specimens, 80 CVS samples were chromosomally normal, had documentation of nuchal translucency > 3.0 mm, and were included in the study at the referring obstetrician's request. None of the 80 fetuses with an increased nuchal translucency and normal karyotype demonstrated a 22q11 microdeletion. By Fisher exact test, the probability of 80 fetuses with excess nuchal translucency having no deletions of chromosome 22 was not significantly different than the expected rate of 0.18% (P value = 1). CONCLUSION: Routine 22q11 microdeletion analysis for fetuses with excess nuchal translucency is not indicated. Instead, we recommend storing an extra unbanded slide from the cultured CVS material to permit 22q11 FISH analysis should a cardiac malformation be identified later by fetal echocardiography.

Chromosomal abnormalities among 246 fetuses with pleural effusions detected on prenatal ultrasound examination: factors associated with an increased risk of aneuploidy.

PURPOSE: To determine the prevalence of chromosomal abnormalities in fetuses with prenatally diagnosed pleural effusions and to identify factors associated with an increased risk of aneuploidy. METHODS: A retrospective analysis of the Genzyme Genetics database was performed for samples submitted from October 1994 to April 2003 with an indication of fetal pleural effusion. RESULTS: There were 246 samples in which pleural effusion was identified as an indication for prenatal chromosome analysis. Ninety-four were from fetuses with isolated pleural effusions and 152 had other abnormalities in addition to pleural effusion. The prevalence of chromosome abnormalities was 35.4% (95% confidence interval, 29.2-41.4%). Among the eight first trimester samples, the aneuploidy rate was 63%. Pleural effusion cases associated with additional sonographic findings had a significantly higher aneuploidy rate than the isolated pleural effusion cases (50% vs. 12%, P < 0.001). CONCLUSIONS: Chromosome analysis is warranted after the prenatal detection of a fetal pleural effusion. The risk of aneuploidy is greater with first trimester detection and is significantly increased in the presence of other associated anomalies.

Fragile X syndrome carrier screening in the prenatal genetic counseling setting.

PURPOSE: To document our experience with fragile X carrier screening. METHODS: In this study, 29,103 women with no known or suspected family history of fragile X syndrome were offered fragile X carrier screening during their prenatal genetic counseling visit. Screening acceptance was analyzed by referral indication, carrier frequencies documented, and prenatal outcome data presented. RESULTS: Overall, 7.9% accepted carrier screening. The premutation frequency was 1 in 382, and the intermediate allele frequency was 1 in 143. CONCLUSIONS: Fragile X screening is a desirable option for some women seeking prenatal genetic counseling and should be made available to this population.

Sequential Down syndrome screening: the importance of first and second trimester test correlations when calculating risk.

Down syndrome screening can be particularly effective when both first and second trimester tests are performed. However, the counseling of women who have received sequential first and second trimester screening can be problematic. We evaluated an approximation where the post-test risk from the first trimester screening is used as the new a priori risk for the second trimester screening. The approximation disregards between-trimester test correlations. The Down syndrome detection rate based on the approximation (90.2%) would be close to that obtained when all correlations were considered (90.8%) but the false positive rate would be 26% higher (3.9% versus 3.1%, respectively). For any particular woman, the use of the approximation could result in highly inaccurate risks. We conclude that the correlations that exist between first and second trimester screening tests preclude the use of second trimester risks derived from the direct product of separate first and second trimester screening. Counseling issues in the delivery of sequential screening are discussed.

Cytogenetics and molecular cytogenetics in prenatal diagnosis.

Prenatal chromosome diagnosis has been a rapidly changing field over the past 10 years for both sampling methodologies and molecular techniques to complement chromosome analysis. This review summarizes current techniques used by the clinician and their risks, and selected aspects of cytogenetic and molecular techniques used by the laboratories. Within the next 3 to 5 years, DNA techniques are expected to complement, and potentially replace, aspects of current cytogenetic and FISH techniques, and provide more detailed information on the genetic status of the fetus.

Biochemical screening for aneuploidy in ovum donor pregnancies.

OBJECTIVE: The purpose of this study was to compare the screening efficacy for aneuploidy detection in ovum donor pregnancies with the use of either the age of the ovum donor or the ovum recipient. STUDY DESIGN: Second-trimester biochemical screening for aneuploidy with alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin was performed on maternal serum samples that were submitted prospectively from singleton ovum donor pregnancies. The calculation of aneuploidy risks were performed separately with the age of the ovum donor or the ovum recipient. Risks of >1 in 295 and >1 in 100 were used as cutoff values for the identification of screen-positive pregnancies for Down syndrome and trisomy 18, respectively. RESULTS: Samples from 93 ovum donor pregnancies were identified. The mean ages of the ovum donors and recipients were 27 years (range 20-38.5 years) and 43.6 years (range, 25.9-54.3 years), respectively. When the age of the ovum donor was used in the determination of aneuploidy risk, there were 9 screenpositive pregnancies (9.7%), whereas the use of the age of the ovum recipient resulted in 76 screen-positive pregnancies (82%). With the use of the McNemar test for paired observations, the proportion of screenpositive pregnancies with the age of the ovum donor (9.7%) compared with the age of the ovum recipient (82%) was statistically significant (P <.0001). The odds of being affected, given a positive result, were 1 in 9 (11%) with the age of the ovum recipient and 1 in 76 (1.3%) with the age of the ovum donor. The only fetus with aneuploidy (trisomy 18) was identified as being screen positive in both the ovum donor and ovum recipient calculations. CONCLUSION: In ovum donor pregnancy aneuploidy risk calculations, the use of the age of the ovum donor instead of the ovum recipient reduces the false-positive rate and improves screening efficacy.

Prenatal diagnosis from fetal urine in bladder outlet obstruction: success rates for traditional cytogenetic evaluation and interphase fluorescence in situ hybridization.

PURPOSE: To determine the optimal approach to the prenatal chromosome analysis of fetal urine from fetuses with bladder outlet obstruction. METHODS: Retrospective evaluation of traditional cytogenetic and interphase fluorescence in situ hybridization (FISH) analysis on fetal urine specimens from fetuses with bladder outlet obstruction. RESULTS: Traditional cytogenetic analysis was successful on 71 (95%) of 75 samples, and FISH was informative on 20 (65%) of 31 specimens. The combination of traditional cytogenetic analysis and FISH yielded a 96% diagnostic success rate. The mean turnaround time was 8 days (range 5-14) for traditional cytogenetic analysis and 1.6 days (range 1.0-4.0) for FISH. Chromosome abnormalities were detected in 6 (7.9%) of 76 pregnancies. CONCLUSION: Traditional cytogenetic analysis achieves a high success rate (95%) and is superior to FISH for chromosome evaluation of fetal urine. However, FISH, when informative, can complement traditional cytogenetics as it will expeditiously rule out common trisomies in fetuses with bladder outlet obstruction.