The role of reanalyses in genomic sequencing for fetal effusions.
Explore the source record for details and available documents.
Letter↗
Biomedical subjects
Mary E Norton
Publications and source records attributed to Mary E Norton.
Diagnostic Yield After Postnatal Reanalysis of Prenatal Exome Sequencing Results.
OBJECTIVE: Analysis of exome sequencing (ES) relies on correlation with phenotypic features, but fetal phenotyping is often incomplete. The additional yield of postnatal follow-up in cases with negative or inconclusive prenatal ES has not been demonstrated. Our objective was to assess the incremental diagnostic yield of ES reanalysis after initially negative prenatal ES for congenital anomalies incorporating features identified postnatally. METHODS: This was a secondary analysis of two prospective cohort studies of ES for fetal anomalies. We included cases in which initial ES utilizing the prenatal phenotype was not diagnostic. The primary outcome was incremental diagnostic yield of ES when incorporating postnatal findings. RESULTS: Eighty-seven cases with negative or inconclusive prenatal ES and postnatal follow-up available were included. Of those, 56 (64%) had new findings postnatally. There was an incremental yield of 2% in the entire cohort, and 7% in those with new postnatal findings. In two additional cases, postnatal evaluation suggested a specific genetic diagnosis that was not detectable with ES. CONCLUSION: Among pregnancies with fetal anomalies and no clear diagnosis identified by prenatal ES, postnatal follow-up is recommended. Reanalysis of ES results can result in a genetic diagnosis in 7% of cases with new findings.
Humans↗
Unequal placental sharing and birth weight discordance in monochorionic diamniotic twins.
OBJECTIVE: The purpose of this study was to define the association between unequal placental sharing and birth weight discordance in monochorionic/diamniotic twin pregnancies. STUDY DESIGN: The study comprised a prospective cohort of monochorionic/diamniotic twin pregnancies who were delivered in Kaiser Permanente-Northern California, 1997-2003. Dye injection studies of fresh postpartum placentas were performed. Placental sharing, cord insertion combinations, vascular anastomoses, gestational age, and birth weights were recorded. Statistical comparisons of birth weight and gestational age were made with the Student t test. Rates of birth weight discordance were compared with the chi-square test. Multivariate logistic regression models analyzed the relationship between variables of interest. RESULTS: Mean birth weights for larger and smaller twins were 2400 g and 2109 g, respectively. Twenty-two percent of the monochorionic/diamniotic twin pairs had birth weight discordance > or = 20%, and 8% of these pairs had twin-twin transfusion syndrome. Monochorionic/diamniotic twin pairs with unequal placental sharing had a 9.8 times greater likelihood of birth weight discordance (95% CI, 5.4-17.9) as compared with those pairs with equal placental sharing. CONCLUSION: Unequal placental sharing is a significant risk factor for birth weight discordance in monochorionic/diamniotic twins. Antenatal diagnosis of unequal placental sharing would enable improved counseling in the setting of monochorionic/diamniotic twins.
Amnion↗
Prenatal diagnosis of familial type I choledochal cyst.
Familial choledochal cysts are extremely rare. High-resolution ultrasound now allows for the antenatal diagnosis of these anomalies. After delivery, elective surgical resection should be planned; however, increases in size, deterioration of liver function, and ascending cholangitis frequently force early intervention. We report an unusual occurrence of siblings with type I choledochal cysts and review the existing literature on cause, genetics, classification, diagnosis, and management of this disease.
Child↗
Ultrasound screening of fetuses at increased risk for Down syndrome: how many missed diagnoses?
OBJECTIVE: To determine the number of Down syndrome (DS) fetuses identified, amniocenteses performed, and procedure-related losses incurred when second-trimester ultrasound is used to screen high-risk patients in order to determine who should undergo an amniocentesis. METHODS: A decision analytic model was designed for women at increased risk for a DS fetus due to either advanced maternal age (AMA) or a positive expanded maternal serum alpha fetoprotein (MSAFP) screening test, also known as a triple screen (+triple) test. The model compared: (1) the current standard of offering all at-risk women amniocentesis to (2) a policy of performing amniocentesis only when sonographic markers of DS are seen on ultrasound. Baseline assumptions included a sensitivity of 60.6% for targeted ultrasound and a screen-positive rate of 16.2%. RESULTS: If targeted ultrasound is used to determine whether high-risk patients should undergo amniocentesis, 56% (3933/7025) of all DS fetuses are missed. The diagnosis of DS is missed most frequently among women at highest risk for DS (AMA and +triple). In this subgroup of patients, there are 3152 DS fetuses in the second trimester, of which 2815 (89%) are identified by triple screen test. When an ultrasound screen is added, only 1709 (54%) of DS fetuses will be identified. CONCLUSION: Substantially fewer DS fetuses will be detected when targeted ultrasound is used as a screen among already identified high-risk patients.
Decision Support Techniques↗
Variation in the decision to terminate pregnancy in the setting of fetal aneuploidy.
OBJECTIVE: To investigate the rate of pregnancy termination for various fetal aneuploidies, and to evaluate predictors of this choice. METHODS: A retrospective cohort study identified all patients with any of seven common fetal aneuploidies (trisomies 21, 18, and 13; 45,X, 47,XXX, 47,XXY, and 47,XYY) at a referral prenatal diagnosis unit from 1983 to 2003. We abstracted type of aneuploidy, time and type of diagnostic procedure, maternal age, and ethnicity as predictors of the decision to terminate. Statistical comparisons were made using the chi-square test. Potential confounding variables were controlled for using multivariate logistic regression. RESULTS: Overall, there were 833 patients who had fetuses with aneuploidy. In our study population, the overall rate of termination was 81%: 86% in cases of autosomal trisomy and 60% in cases of sex chromosome aneuploidy (SCA) (p < 0.001). Rates were lowest in cases with the least severe prognosis, 47,XYY (57%) and 47,XXX (40%) compared with 45,X (65%) and 47,XXY (70%) (p = 0.05). Patients with SCA detected by chorionic villus sampling (CVS) had a higher termination rate than those who had undergone amniocentesis (77% vs 55%, p = 0.015). Increased maternal age was associated with higher termination rates in autosomal trisomy (88% vs 76% p < 0.001) and a trend toward decreased rates in those with SCA (55% vs 71%, p = 0.06). Hispanic women were less likely to terminate pregnancy (69%, p = 0.01) than those from other racial/ethnic groups. CONCLUSION: Type and severity of aneuploidy, type of diagnostic procedure, maternal age, and ethnicity contribute to patients' decision-making in the setting of fetal aneuploidy.
Abortion, Eugenic↗
History of miscarriage and increased incidence of fetal aneuploidy in subsequent pregnancy.
OBJECTIVE: The purpose of this study was to examine the association between history of spontaneous abortion and aneuploidy in a subsequent pregnancy. METHODS: This was a retrospective cohort study of women who underwent fetal karyotype analysis with amniocentesis or chorionic villus sampling at a single prenatal diagnosis center. Information on spontaneous abortions, parity, maternal age, ethnicity, type of prenatal diagnosis, and karyotype was assessed. Univariable and multivariable analyses were conducted. RESULTS: A total of 46,939 women were included in our analysis. Women with no prior spontaneous abortions had a 1.39% risk for any aneuploidy. In women with one prior spontaneous abortion, this risk increased to 1.67%; for women with 2 previous spontaneous abortions, the risk increased to 1.84%; and for those women who had had 3 or more prior spontaneous abortions, the risk increased further to 2.18% (P < .007). When controlling for maternal age, parity, ethnicity, and mode of prenatal diagnosis and compared with women with no prior spontaneous abortions, women with one prior spontaneous abortion (adjusted odds ratio [AOR] 1.21, 95% confidence interval [CI] 1.01-1.47) or 3 or more prior spontaneous abortions (AOR 1.51, 95% CI 1.02-2.25) had a statistically significant increase in aneuploidy in a subsequent pregnancy. Women with 2 prior spontaneous abortions had an AOR of 1.26 for aneuploidy, but the 95% CI contained unity. CONCLUSION: An increased risk of karyotypic abnormality identified at the time of prenatal diagnosis is demonstrated in patients with an increasing number of spontaneous abortions. This study provides information regarding this risk among women presenting for prenatal diagnosis. According to our data, for a woman with an a priori risk of 1 in 300 for Down syndrome, 3 prior spontaneous abortions would increase that risk by 47% to 1 in 204. These results should be confirmed in low-risk populations.
Abortion, Spontaneous↗
Chorionic villus sampling compared with amniocentesis and the difference in the rate of pregnancy loss.
OBJECTIVE: To compare loss rates following amniocentesis and chorionic villus sampling (CVS) over time. METHODS: A retrospective cohort study of all amniocentesis and CVS procedures resulting in a normal karyotype from 1983-2003 at a single prenatal diagnostic referral center was conducted. Pregnancy loss rates for amniocentesis, CVS, and nonintervention groups (ie, those who had nuchal translucency screening or counseling, but no procedure) were compared using the chi 2 test. Year of procedure, maternal age, parity, race or ethnicity, and gestational age at procedure were controlled for in multivariable logistic regression models. RESULTS: There were 9,886 CVS and 30,893 amniocentesis procedures performed during the study period that resulted in a normal karyotype. The overall loss rates were 3.12% for CVS and 0.83% for amniocentesis (P < .001). When examined by 5-year intervals, there was a statistically significant decrease in the CVS loss rate (P < .001) and a nonsignificant lesser decrease in the loss rate for amniocentesis over time. Although the pregnancy loss rate from CVS over the entire study period was higher than from amniocentesis (adjusted odds ratio 4.23, 95% confidence interval 2.29-7.81), in the most recent time period, 1998 to 2003, there was no difference between the two procedures (adjusted odds ratio 1.03, 95% confidence interval 0.23-4.52). CONCLUSION: The loss rates for both amniocentesis and CVS at our institution have decreased over time. Because the decrease in loss rate for CVS has been greater, there is no longer a statistically significant difference between the two. These results are informative in both patient counseling and establishing widespread prenatal diagnostic and screening programs.
Abortion, Spontaneous↗
Prenatal testing guidelines: time for a new approach.
Numerous advances over the past 15 years have led to a much wider array of prenatal testing options for pregnant women who are interested in obtaining information regarding the chromosomal status of their fetus. However, despite recent data calling into question the assumptions underlying current testing guidelines, including those inherent in the risk-based threshold for offering invasive testing, chorionic villus sampling and amniocentesis are still typically offered only to women whose likelihood of carrying a fetus affected by a chromosomal disorder such as Down syndrome is at least as high as that of the average 35-year-old. In this paper, we summarize the evidence suggesting that this aspect of prenatal testing guidelines should be revisited, and that women should be allowed to make informed decisions regarding the use of invasive testing that are reflective of their own values and preferences.
Congenital Abnormalities↗
Prenatal diagnosis of minute supernumerary marker chromosomes.
The identification of supernumerary marker chromosomes (SMC) at prenatal diagnosis is problematic, particularly for the prediction of phenotype. The assessment of phenotypic risk is based on the size, morphology and origin of the SMC. Fluorescence in situ hybridization (FISH) characterization and family studies are also employed to aid in determining the significance of a prenatally ascertained SMC. Generally, SMC containing euchromatin are more likely to be associated with abnormal phenotypes and SMC without euchromatin are more likely to result in normal phenotypes. The smallest of SMC, minute SMC (minSMC) appear as dot-like or centric fragments and are particularly difficult to identify and characterize. Previous empirical observations suggested that the risk of phenotypic abnormality in prenatally ascertained minSMC was < or = 5%. We identified minSMC in chorionic villus samples (CVS) or amniocytes from 11 unrelated pregnancies. The chromosomal origin of each minSMC was identified by sequential FISH analysis with chromosome-specific centromere probes. Further FISH analysis with whole chromosome paint probes was undertaken to assess each minSMC for the presence or absence of euchromatin, since the presence of euchromatin may be associated with a higher risk of abnormality. Two minSMC were shown to have euchromatin. The first, a minSMC(12) was found in CVS but not confirmed in amniocytes, indicating confined placental mosaicism. The second, a minSMC derived from chromosome 19, was associated with ultrasound abnormalities. Apart from a case with mild speech delay, the remaining minSMC cases without detectable euchromatin had a normal outcome at birth and/or on longer term follow-up. Additional FISH analyses with a telomeric repeat probe showed no signal on any of the minSMC tested, suggesting that they were ring chromosomes in structure. These data further support the concept that minSMC containing euchromatin are more likely to be associated with an abnormal phenotype, although as more data are collected, this may vary by chromosome of origin. The absence of detectable euchromatin, while not guaranteeing a normal result, is most likely to have a normal outcome. The present report and previous studies do not yet allow any significant adjustment of the empirical < or = 5% risk estimate for minSMC identified at prenatal diagnosis. However, reporting of additional cases with characterization of the minSMC and particularly with long-term follow-up will, in time, allow for more accurate risk estimates and provide prognostic information.
Adult↗
Y chromosome heterochromatin variation detected at prenatal diagnosis.
Explore the source record for details and available documents.
Adult↗
Prenatal diagnosis of polymicrogyria by fetal magnetic resonance imaging in monochorionic cotwin death.
Explore the source record for details and available documents.
Adult↗
Fetal magnetic resonance imaging in the evaluation of fetuses referred for sonographically suspected abnormalities of the corpus callosum.
OBJECTIVE: Fetal magnetic resonance imaging (MRI) has been shown to be useful in assessing the developing central nervous system. However, its utility in specific brain disorders has not been well investigated. We hypothesized that fetal MRI can better assess the integrity of the brain in cases with sonographically suspected callosal abnormalities. METHODS: We retrospectively reviewed fetal MRI and prenatal sonographic studies of 10 fetuses referred for MRI for sonographically suspected callosal abnormalities. RESULTS: An abnormal corpus callosum was identified on fetal MRI in 80% of cases. The type of callosal abnormality (complete or partial agenesis) was similar on both prenatal sonography and fetal MRI in all cases. All sonographically identified additional brain abnormalities were detected on fetal MRI, with the exception of choroid plexus cysts. Furthermore, in 63% (5 of 8) of cases with a callosal abnormality on both sonography and fetal MRI, additional brain abnormalities were detected on fetal MRI that were not apparent on sonography. These sonographically occult findings were confirmed on postnatal MRI or autopsy in 3 of 5 patients. CONCLUSIONS: Fetal MRI is an important adjunct to sonography in assessing the corpus callosum and other aspects of brain development when agenesis of the corpus callosum is suspected. It can identify frequent additional findings that are not visible on sonography such as abnormal sulcation. In light of the association between additional brain abnormalities and worse neurodevelopmental outcome, the potential of fetal MRI as an important adjunctive prognostic imaging test in fetuses with callosal agenesis can now be tested.
Agenesis of Corpus Callosum↗
Rapid prenatal diagnosis in translocation carriers by interphase FISH with chromosome-specific subtelomere probes.
Interphase fluorescence in situ hybridization (FISH) analysis can provide rapid preliminary analysis of chromosome aneuploidy from direct amniocyte and chorionic villus sample (CVS) preparations. Typically, interphase FISH is used in screening for numerical abnormalities of chromosomes X, Y, 13, 18, and 21. More recently, FISH probe sets became available for the subtelomeric region of each chromosome, allowing screening for terminal chromosome rearrangements. The purpose of the current study was to evaluate the use of dual-color interphase FISH analysis with chromosome-specific subtelomere probes for rapid prenatal diagnosis in 14 pregnancies from 12 different translocation carriers. Interphase FISH analysis was performed on direct CVS or amniocyte preparations from 12 reciprocal translocation and two Robertsonian translocation pregnancies with the appropriate chromosome-specific subtelomere probes for each chromosome involved in the translocation. Analysis of the interphase FISH probe signals predicted balanced or normal segregants in each case, thus rapidly excluding a chromosomally unbalanced segregant. Subsequent metaphase analysis showed normal karyotypes in seven fetuses and balanced translocations in the remaining seven. This series illustrates the utility of interphase FISH analysis with chromosome-specific subtelomere probes for rapid prenatal diagnosis in cases of parental reciprocal translocations and Robertsonian translocations.
Amniocentesis↗
Ring 21 chromosome and a satellited 1p in the same patient: novel origin for an ectopic NOR.
Nucleolus organizer regions (NORs) are present on the satellite stalks located on the short arms of the acrocentric chromosomes. NORs present on non-acrocentric chromosomes (ectopic NORs) are rare and were reported in both phenotypically normal and abnormal individuals. We describe a patient, ascertained prenatally, with an ectopic NOR on 1p and a ring 21 chromosomes. Amniocentesis was performed at 27-weeks gestation on a 19-year-old woman after identification of intrauterine growth retardation (IUGR) by ultrasound. Cytogenetic analysis of amniocytes from the fetus showed a mos 46,XX,1ps,r(21) (p11.2q22.3)[44]/45,XX,1ps,-21[6] karyotype. Parental karyotypes were normal, indicating a de novo origin for these rearrangements in the fetus. Molecular cytogenetic characterization of the 1ps showed no loss of euchromatin and retention of the telomeric repeats. Characterization of the r(21) using array comparative genomic hybridization (CGH) identified that the deletion was approximately 5 Mb encompassing most of chromosome band 21q22.3. The ectopic NOR (1ps) was most likely derived from the acentric 21p fragment generated by the chromosome breakage event that lead to formation of the r(21) chromosome. This represents a novel mechanism for the origin of ectopic NORs. In addition, this study illustrates the importance of FISH analysis with telomeric and subtelomeric probes for characterization of chromosomes with ectopic NORs.
Chromosomes, Human, Pair 1↗
Nuchal translucency and first trimester biochemical markers for down syndrome screening: a cost-effectiveness analysis.
OBJECTIVE: The purpose of this study was to perform a cost-effectiveness analysis that compared the first- and second- trimester screening tools for Down syndrome. STUDY DESIGN: A decision tree was designed that compared four possible screens for Down syndrome: (1) current second- trimester expanded maternal serum alpha-fetoprotein test (AFP), (2) first-trimester nuchal translucency screen, (3) first-trimester serum screen, and (4) combined first-trimester screen with both nuchal translucency screen and a serum screen. Incremental cost-benefit and cost-effectiveness ratios were calculated that compared the first-trimester screens with expanded alpha-fetoprotein. RESULTS: The combined screen (nuchal translucency screen + first-trimester serum screen) identified 3,833 Down syndrome fetuses, the nuchal translucency alone identified 3,413 Down syndrome fetuses, and the first- trimester serum screen identified 2,993 Down syndrome fetuses. Each of these screens was an improvement over the current expanded AFP screen, which diagnosed 2,446 Down syndrome fetuses. It would cost $98,381 for each additional Down syndrome case that would be identified by nuchal translucency alone, with a benefit-to-cost ratio of 4.85. The addition of the first-trimester serum screen is still cost-effective compared with expanded AFP; the cost would be $319,934 for each additional Down syndrome fetus who was identified, which would be a benefit-to-cost ratio of 1.57. CONCLUSION: First-trimester screening for Down syndrome with nuchal translucency screening alone or with serum markers is more clinically effective and cost-effective than the current expanded AFP screen that is being used.
Cost-Benefit Analysis↗
Risk factors for breast cancer in Jordanian women.
PURPOSE: To investigate risk factors associated with breast cancer in Jordanian women. DESIGN: Retrospective case-control study based on data from the Jordanian Cancer Registry, in 1996. METHODS: One hundred women with breast cancer (cases) and 100 women without breast cancer (controls) were interviewed in their homes. A questionnaire was developed in Arabic to investigate the risk factors associated with breast cancer in Jordanian women. FINDINGS: Bivariate analysis indicated significant differences between the cases and controls, including age of menarche and menopause, use of households' pesticides, stressful life events, and direct trauma to the breast. Logistic regression analysis indicated higher odds ratios for breast enlargement, irregular menstruation, use of hair dye, oral contraceptives, and fertility drugs. CONCLUSIONS: Significant differences in correlates of breast cancer were found between the cases and the controls.
Aged↗
Short-term maternal outcomes that are associated with the EXIT procedure, as compared with cesarean delivery.
OBJECTIVE: The ex utero intrapartum treatment procedure was developed to treat iatrogenic tracheal obstruction that resulted from in utero fetal therapy for congenital diaphragmatic hernia. The ex utero intrapartum treatment procedure allows for controlled intubation while the neonate is maintained on placental circulation, prolonging operative time. This study evaluates whether there is increased maternal morbidity associated with this procedure compared with routine cesarean deliveries. STUDY DESIGN: Maternal outcomes on 34 patients who underwent the ex utero intrapartum treatment procedure were evaluated. Infection rate, estimated blood loss, need for transfusion, and length of postoperative hospital stay were compared to maternal outcomes from 52 non-laboring patients who underwent non-emergent primary cesarean delivery of singleton fetuses during the same time interval. RESULTS: The rate of chorioamnionitis was similar between groups (26% vs 21%; P =.57). Postpartum wound complications were more common in patients who underwent ex utero intrapartum treatment (15% vs 2%; P =.03), although the rate of endometritis was similar (15% vs 10%; P =.50). Estimated blood loss was higher in the patients who underwent ex utero intrapartum treatment (1104 mL vs 883 mL; P <.001), but there was no difference between groups in hematocrit level change or postpartum hospital stay. CONCLUSION: Women who undergo the ex utero intrapartum treatment procedure experience more wound complications but no difference in postoperative hematocrit level change or postpartum length of stay.
Adult↗