Medicine › Pediatrics, Perinatology and Child Health

Prenatal Screening and Diagnostics

Description

This cluster of papers focuses on the various techniques and methods for diagnosing and screening prenatal aneuploidy, including the use of maternal plasma DNA sequencing, noninvasive prenatal testing, preimplantation genetic diagnosis, and fetal DNA analysis. It also covers topics such as chromosomal abnormalities, trisomy detection, and genomic sequencing in the context of prenatal diagnosis.

Keywords

Prenatal Diagnosis; Aneuploidy Screening; Maternal Plasma DNA Sequencing; Noninvasive Prenatal Testing; Chromosomal Abnormalities; Preimplantation Genetic Diagnosis; Fetal DNA Analysis; Cell-Free DNA; Trisomy Detection; Genomic Sequencing

Rich with the voices and stories of participants, these touching, firsthand accounts examine how women of diverse racial, ethnic, class and religious backgrounds perceive prenatal testing, the most prevalent and … Rich with the voices and stories of participants, these touching, firsthand accounts examine how women of diverse racial, ethnic, class and religious backgrounds perceive prenatal testing, the most prevalent and routinized of the new reproducing technologies. Based on the author's decade of research and her own personal experiences with amniocentesis, Testing Women, Testing the Fetus explores the "geneticization" of family life in all its complexity and diversity.
This Article considers the influence and implications of the application of genetic technologies to definitions of disease and to the treatment of illness. The concept of ā€œgeneticizationā€ is introduced to … This Article considers the influence and implications of the application of genetic technologies to definitions of disease and to the treatment of illness. The concept of ā€œgeneticizationā€ is introduced to emphasize the dominant discourse in today's stories of health and disease and the social construction of biological phenomenon is described. The reassurance, choice and control supposedly provided by prenatal genetic testing and screening are critically examined, and their role in constructing the need for such technology is addressed. Using the stories told about prenatal diagnosis as a focus, the consequences of a genetic perspective for and on women and their health care needs are explored.
OBJECTIVE--To examine the significance of fetal nuchal translucency at 10-14 weeks9 gestation in the prediction of abnormal fetal karyotype. DESIGN--Prospective screening study. SETTING--The Harris Birthright Research Centre for Fetal Medicine, … OBJECTIVE--To examine the significance of fetal nuchal translucency at 10-14 weeks9 gestation in the prediction of abnormal fetal karyotype. DESIGN--Prospective screening study. SETTING--The Harris Birthright Research Centre for Fetal Medicine, King9s College Hospital, London. SUBJECTS--827 fetuses undergoing first trimester karyotyping by amniocentesis or chorionic villus sampling. MAIN OUTCOME MEASURE--Incidence of chromosomal defects. RESULTS--The incidence of chromosomal defects was 3% (28 of 827 cases). In the 51 (6%) fetuses with nuchal translucency 3-8 mm thick the incidence of chromosomal defects was 35% (18 cases). In contrast, only 10 of the remaining 776 (1%) fetuses were chromosomally abnormal. CONCLUSION--Fetal nuchal translucency > or = 3 mm is a useful first trimester marker for fetal chromosomal abnormalities.
Summary Cytogenetic analysis of 1000 spontaneous abortions showed 463 to have an abnormal chromosome constitution. The proportion of chromosome abnormalities varied with the gestational age of the abortus and the … Summary Cytogenetic analysis of 1000 spontaneous abortions showed 463 to have an abnormal chromosome constitution. The proportion of chromosome abnormalities varied with the gestational age of the abortus and the type of tissue cultured but was not significantly different among the five racial groups represented in the study population. It was suggested that differences in the rate of chromosome abnormalities among cytogenetic studies of spontaneous abortions were the result of methodological differences in sample selection rather than real biological variation among study populations. The only factor found to be unequivocally associated with the aetiology of chromosome abnormalities in spontaneous abortions was increasing maternal age in trisomies.
In an ultrasound screening study at 10 to 14 weeks of gestation for measurement of fetal nuchal translucency thickness there were 102 monochorionic and 365 dichorionic twin pregnancies. In the … In an ultrasound screening study at 10 to 14 weeks of gestation for measurement of fetal nuchal translucency thickness there were 102 monochorionic and 365 dichorionic twin pregnancies. In the monochorionic compared with the dichorionic pregnancies there was a higher rate of fetal loss before 24 weeks of gestation (12.2% versus 1.8%), perinatal mortality (2.8% versus 1.6%), prevalence of delivery before 32 weeks (9.2% versus 5.5%), and prevalence of birthweight below the 5th centile in both twins (7.5% versus 1.7%). However, the proportion of pregnancies with a birthweight discordancy of more than 25% was similar in the two groups (11.3% versus 12.1%).
Rare nucleated fetal cells circulate within maternal blood. Noninvasive prenatal diagnosis by isolation and genetic analysis of these cells is currently being undertaken. We sought to determine if genetic evidence … Rare nucleated fetal cells circulate within maternal blood. Noninvasive prenatal diagnosis by isolation and genetic analysis of these cells is currently being undertaken. We sought to determine if genetic evidence existed for persistent circulation of fetal cells from prior pregnancies. Venous blood samples were obtained from 32 pregnant women and 8 nonpregnant women who had given birth to males 6 months to 27 years earlier. Mononuclear cells were sorted by flow cytometry using antibodies to CD antigens 3, 4, 5, 19, 23, 34, and 38. DNA within sorted cells, amplified by PCR for Y chromosome sequences, was considered predictive of a male fetus or evidence of persistent male fetal cells. In the 32 pregnancies, male DNA was detected in 13 of 19 women carrying a male fetus. In 4 of 13 pregnancies with female fetuses, male DNA was also detected. All of the 4 women had prior pregnancies; 2 of the 4 had prior males and the other 2 had terminations of pregnancy. In 6 of the 8 nonpregnant women, male DNA was detected in CD34+CD38+ cells, even in a woman who had her last son 27 years prior to blood sampling. Our data demonstrate the continued maternal circulation of fetal CD34+ or CD34+CD38+ cells from a prior pregnancy. The prolonged persistence of fetal progenitor cells may represent a human analogue of the microchimerism described in the mouse and may have significance in development of tolerance of the fetus. Pregnancy may thus establish a long-term, low-grade chimeric state in the human female.
Recent advances in recombinant DNA technology have made possible the molecular analysis and prenatal diagnosis of several human genetic diseases. Fetal DNA obtained by aminocentesis or chorionic villus sampling can … Recent advances in recombinant DNA technology have made possible the molecular analysis and prenatal diagnosis of several human genetic diseases. Fetal DNA obtained by aminocentesis or chorionic villus sampling can be analyzed by restriction enzyme digestion, with subsequent electrophoresis, Southern transfer, and specific hybridization to cloned gene or oligonucleotide probes. With This disease results from homozygosity of the sickle-cell allele (rS) at the 3globin gene locus. The S allele differs from the wild-type allele (3A) by substitution of an A in the wild-type to a T at the second position of the sixth codon of the p chain gene, resulting in the replacement of a glutamic acid by a valine in the expressed protein. For the prenatal diagnosis of sickle cell anemia, DNA ob-
The clinical manifestations of Fanconi’s anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents … The clinical manifestations of Fanconi’s anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi’s anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7]. We report here on hematopoietic reconstitution in a boy with severe Fanconi’s anemia who received cryo-preserved umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifically for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9,10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling. This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis – a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]).
To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome … To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies.Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 4 January 2015.In total, 37 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.2% (95% CI, 98.5-99.6%) and 0.09% (95% CI, 0.05-0.14%), respectively, for trisomy 21, 96.3% (95% CI, 94.3-97.9%) and 0.13% (95% CI, 0.07-0.20) for trisomy 18, 91.0% (95% CI, 85.0-95.6%) and 0.13% (95% CI, 0.05-0.26%) for trisomy 13, 90.3% (95% CI, 85.7-94.2%) and 0.23% (95% CI, 0.14-0.34%) for monosomy X and 93.0% (95% CI, 85.8-97.8%) and 0.14% (95% CI, 0.06-0.24%) for sex chromosome aneuploidies other than monosomy X. For twin pregnancies, the DR for trisomy 21 was 93.7% (95% CI, 83.6-99.2%) and the FPR was 0.23% (95% CI, 0.00-0.92%).Screening for trisomy 21 by analysis of cfDNA in maternal blood is superior to that of all other traditional methods of screening, with higher DR and lower FPR. The performance of screening for trisomies 18 and 13 and sex chromosome aneuploidies is considerably worse than that for trisomy 21.
The possibility of improving the effectiveness of antenatal screening for Down's syndrome by measuring human chorionic gonadotrophin concentrations in maternal serum during the second trimester to select women for diagnostic … The possibility of improving the effectiveness of antenatal screening for Down's syndrome by measuring human chorionic gonadotrophin concentrations in maternal serum during the second trimester to select women for diagnostic amniocentesis was examined. The median maternal serum human chorionic gonadotrophin concentration in 77 pregnancies associated with Down's syndrome was twice the median concentration in 385 unaffected pregnancies matched for maternal age, gestational age, and duration of storage of the serum sample. Measuring human chorionic gonadotrophin in maternal serum was an effective screening test, giving a lower false positive rate (3%) at a 30% detection rate than that for maternal age (5%) and the two existing serum screening tests, unconjugated oestriol (7%) and alpha fetoprotein (11%). The most effective screening results were obtained with all four variables combined; at the same 30% detection rate the false positive rate declined to 0.5%. The new screening method would detect over 60% of affected pregnancies, more than double that achievable with the same amniocentesis rate in existing programmes (5%), and could reduce the number of children born with Down's syndrome in the United Kingdom from about 900 a year to about 350 a year.
The seventh report of the ESHRE PGD Consortium is presented documenting cycles collected for the calendar year 2004 and follow-up of the pregnancies and babies born subsequent to these cycles … The seventh report of the ESHRE PGD Consortium is presented documenting cycles collected for the calendar year 2004 and follow-up of the pregnancies and babies born subsequent to these cycles up to October 2005. Since the beginning of the data collections, there has been a steady increase in the number of cycles, pregnancies and babies reported. For data collection VII, 45 centres have participated, reporting on 3358 cycles to oocyte retrieval (OR), 679 pregnancies and 528 babies born. Five hundred and fifty nine OR were reported for chromosomal abnormalities, 113 OR for sexing for X-linked diseases, 520 OR for monogenic diseases, 2087 OR for PGS, and 79 OR for social sexing. Data VII is compared with the cumulative data for data collections I-VI.
Significance Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA, we obtained a bird’s eye view of the identities and contributions … Significance Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA, we obtained a bird’s eye view of the identities and contributions of these tissues to the circulating DNA pool. The tissue contributors and their relative proportions are identified by a bioinformatics deconvolution process that draws reference from DNA methylation signatures representative of each tissue type. We validated this approach in pregnant women, cancer patients, and transplant recipients. This method also allows one to identify the tissue of origin of genomic aberrations observed in plasma DNA. This approach has numerous research and diagnostic applications in prenatal testing, oncology, transplantation monitoring, and other fields.
<h3>Abstract</h3> <b>Objective:</b> To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman9s reproductive history. <b>Design:</b> Prospective register linkage study. <b>Subjects:</b> … <h3>Abstract</h3> <b>Objective:</b> To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman9s reproductive history. <b>Design:</b> Prospective register linkage study. <b>Subjects:</b> All women with a reproductive outcome (live birth, stillbirth, spontaneous abortion leading to admission to hospital, induced abortion, ectopic pregnancy, or hydatidiform mole) in Denmark from 1978 to 1992; a total of 634 272 women and 1 221 546 pregnancy outcomes. <b>Main outcome measures:</b> Age related risk of fetal loss, ectopic pregnancy, and stillbirth, and age related risk of spontaneous abortion stratified according to parity and previous spontaneous abortions. <b>Results:</b> Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20–24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age. <b>Conclusions:</b> Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.
Trisomy, occurring in at least 4% of pregnancies, is the most common chromosome abnormality in humans. The majority of trisomies are associated with single additional chromosome. The presence of an … Trisomy, occurring in at least 4% of pregnancies, is the most common chromosome abnormality in humans. The majority of trisomies are associated with single additional chromosome. The presence of an additional sex chromosome is often associated with physical, behavioral, and intellectual impairment. The presence of an additional autosome is even more serious, being associated with severe mental and physical retardation and frequently with death in infancy. This review discusses the incidence, parental origin, and etiology of human trisomy. The incidence of trisomy varies widely among different chromosomes. This variation appears to reflect a real difference in the frequency of the primary event leading to trisomy as well as in differential selection. Studies of parental origin have shown a 1st maternal meiotic division error to be the most frequent source of the additional chromosome, regardless of the chromosome involved or the maternal age. Although the magnitude of risk varies among chromosomes, increased maternal age is an important risk factor in trisomy. The incidence of trisomy 21 increases from .05% of livebirths at maternal age 20 years to over 3% of all livebirths at age 45 years. The effect of maternal age is most pronounced in double trisomies. It has been hypothesized that the relationship between increasing maternal age and trisomy is due to a gradient in the fetal ovary that affects chiasma freequency. While the basis for the maternal age effect remains unknown, it is almost certainly due to factors acting at or before conception. Epidemiologic studies suggest that maternal irradiation exposure may also lead to trisomy; however, the effective dosage level and the relationship to maternal age remain unknown. No effect of oral contraceptives, spermicides, or fertility drugs on the incidence of trisomy has been documented to date. Understanding of the mechanisms by which trisomies are produced represents a major challenge for human cytogenetics.
It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements … It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters.
We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure … We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure the over- and underrepresentation of chromosomes from an aneuploid fetus. The sequencing approach is polymorphism-independent and therefore universally applicable for the noninvasive detection of fetal aneuploidy. Using this method, we successfully identified all nine cases of trisomy 21 (Down syndrome), two cases of trisomy 18 (Edward syndrome), and one case of trisomy 13 (Patau syndrome) in a cohort of 18 normal and aneuploid pregnancies; trisomy was detected at gestational ages as early as the 14th week. Direct sequencing also allowed us to study the characteristics of cell-free plasma DNA, and we found evidence that this DNA is enriched for sequences from nucleosomes.
Sequencing plasma DNA from a pregnant woman permits genome-wide scanning for the mutational status of the fetus prenatally and noninvasively. Sequencing plasma DNA from a pregnant woman permits genome-wide scanning for the mutational status of the fetus prenatally and noninvasively.
The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, teaching and research for diagnostic imaging in women's healthcare. The ISUOG … The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, teaching and research for diagnostic imaging in women's healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practices at the time at which they were issued. Although ISUOG has made every effort to ensure that guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. They are not intended to establish a legal standard of care because interpretation of the evidence that underpins the guidelines may be influenced by individual circumstances and available resources. Approved guidelines can be distributed freely with the permission of ISUOG ([email protected]). Ultrasonography is widely used for the prenatal evaluation of growth and anatomy as well as for the management of multiple gestations. The procedure provides diagnostic findings that often facilitate the management of problems arising in later pregnancy. For example, abnormal fetal growth is a leading cause of perinatal morbidity and mortality in both industrialized and developing countries. In 2005, the World Health Organization (WHO) concluded that impaired fetal growth had many causes related to: genetic factors, maternal characteristics such as nutrition, lifestyle including smoking, age and disease; complications of pregnancy; and the physical, social and economic environment1, 2. A mid-trimester fetal ultrasound scan serves as an important baseline against which later scans may be compared for the evaluation of growth and health. Ultrasonography can also be used to detect congenital anomalies3-6. The Eurofetus study7, a multicenter project involving 61 obstetric ultrasound units from 14 European countries, examined the accuracy of routine mid-trimester ultrasonographic examination in unselected populations. Over one half (56%) of 4615 malformations were detected and 55% of major anomalies were identified before 24 weeks of gestation. Although many countries have developed local guidelines for the practice of fetal ultrasonography, there are still many areas of the world where they have not been implemented. Most countries offer at least one mid-trimester scan as part of standard prenatal care, although obstetric practice varies widely around the world. This can be related to the availability of qualified practitioners and equipment, local medical practice and legal considerations; in some countries, insurance-related cost reimbursements strongly influence how routine mid-trimester scans are implemented. Nonetheless, a WHO Study Group stated: ā€˜Worldwide, it is likely that much of the ultrasonography currently performed is carried out by individuals with in fact little or no formal training.’8. The intent of this document is to provide further guidance for healthcare practitioners in the performance of the mid-trimester fetal ultrasound scan. The main objective of a routine mid-trimester fetal ultrasound scan is to provide accurate diagnostic information for the delivery of optimized antenatal care with the best possible outcomes for mother and fetus. The procedure is used to determine gestational age and to perform fetal measurements for the timely detection of growth abnormalities later in pregnancy. Other goals are to detect congenital malformations and multiple pregnancies. - cardiac activity; - fetal number (and chorionicity if multiple pregnancy); - fetal age/size; - basic fetal anatomy; - placental appearance and location. Although many malformations can be identified, it is acknowledged that some may be missed, even with sonographic equipment in the best of hands, or that they may develop later in pregnancy. Before starting the examination, a healthcare practitioner should counsel the woman/couple regarding the potential benefits and limitations of a routine mid-trimester fetal ultrasound scan. Many countries offer at least one routine mid-trimester fetal ultrasound scan. As one example, an imaging workshop organized by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in the United States9 reached a consensus that all pregnant women should be offered an ultrasound scan for the detection of fetal anomalies and pregnancy complications. Serial scans may be helpful for some mothers with risk factors for adverse pregnancy outcome (e.g. hypertension or diabetes) and others may benefit from more detailed scans that are targeted to their specific situation. Repeated or detailed examinations, however, are not considered to be routine scans. A routine mid-trimester ultrasound scan is often performed between 18 and 22 weeks of gestation. This period represents a compromise between dating the pregnancy (more accurate if established earlier) and the timely detection of major congenital anomalies. Countries where pregnancy termination is restricted should balance detection rates against the time needed for counseling and additional investigation. Some centers perform the anatomical survey using transvaginal scanning at approximately 13–16 weeks' gestation. This earlier approach can provide useful information about gestational age as a baseline for growth assessment or determination of chorionicity for twins, but may require special training for the early interpretation of anatomical structures. Individuals who routinely perform obstetric scans should have specialized training for the practice of diagnostic ultrasonography in pregnant women. However, the requirements for this activity may vary depending on the country. - trained in the use of diagnostic ultrasonography and related safety issues; - regularly perform fetal ultrasound scans; - participate in continuing medical education activities; - have established appropriate referral patterns for suspicious or abnormal findings; - routinely undertake quality assurance and control measures. - real time, gray-scale ultrasound capabilities; - transabdominal transducers (3–5-MHz range); - adjustable acoustic power output controls with output display standards; - freeze frame capabilities; - electronic calipers; - capacity to print/store images; - regular maintenance and servicing, important for optimal equipment performance. An examination report should be produced as an electronic and/or a paper document, to be sent to the referring care provider in reasonable time. A sample reporting form is available at the end of this article. Images of standard views (stored either electronically or as printed copies) should also be produced and stored. Motion videoclips are recommended for the fetal heart. Local laws should be followed. Many jurisdictions require image storage for a defined period of time. Prenatal ultrasonography appears to be safe for clinical practice. To date, there has been no independently confirmed study to suggest otherwise. Fetal exposure times should be minimized, using the lowest possible power output needed to obtain diagnostic information, following the ALARA principle (As Low As Reasonably Achievable). More details are available from the ISUOG Safety Statement11. These recommendations represent minimum practice guidelines for the mid-trimester fetal ultrasound scan. Consideration must be given to local circumstances and medical practices. Reasons for deviations from these recommendations should be documented. If the examination cannot be performed completely in accordance with adopted guidelines, the scan should be repeated, at least in part, at a later time, or the patient can be referred to another practitioner. This should be done as soon as possible, to minimize unnecessary patient anxiety and unnecessary delay in the potential diagnosis of congenital anomalies or growth disturbances. Individuals who perform ultrasonographic scans during pregnancy should have referral mechanisms in place to manage suspected or detected abnormalities. A minimum examination, following the guidelines presented herein, should be performed before referring the patient, unless technical factors prevent completion of the initial evaluation. - biparietal diameter (BPD); - head circumference (HC); - abdominal circumference (AC) or diameter; - femur diaphysis length (FDL). Measurements should be performed in a standardized manner on the basis of strict quality criteria15. An audit of results can help to ensure accuracy of techniques with regard to specific reference tables. An image(s) should be taken to document the measurement(s). Examples of still images appropriate for fetal biometry are demonstrated in Figure 1. Standard fetal biometry: sonographic measurements of the biparietal diameter and head circumference (a), the abdominal circumference (b) and the femur diaphysis length (c). In this example, calipers are placed on the outer and inner edges of the skull for BPD measurement (large white dots in (a)); some reference charts have been developed using different caliper placement for this measurement (e.g. outer edge to outer edge of the skull). If gestational age has not already been established at a dating or first-trimester scan, it should be determined at the mid-trimester scan on the basis of fetal head size (BPD and/or HC) or FDL. The chosen reference standards should be indicated in the report16. Subsequent scans should not be used to calculate a new estimated date of confinement if age has already been established by a high-quality scan earlier in the pregnancy. Additional measurements, optimally at least 3 weeks from a preceding scan, are usually reported as deviations from mean values with their expected ranges for a given age. This information can be expressed as Z-scores, percentile reference ranges or on a graph, although the degree of deviation from normal at this early stage of pregnancy that would justify action (e.g. a follow-up scan to assess fetal growth or fetal chromosomal analysis) has not been firmly established. Combining measurements significantly improves accuracy compared with prediction based on HC alone17. However, the clinical significance of this improvement is marginal because the improved accuracy represents less than 1 day18. - Cross-sectional view of the fetal head at the level of the thalami; - ideal angle of insonation is 90° to the midline echoes; - symmetrical appearance of both hemispheres; - continuous midline echo (falx cerebri) broken in middle by the cavum septi pellucidi and thalamus; - no cerebellum visualized. Both calipers should be placed according to a specific methodology, because more than one technique has been described (e.g. outer edge to inner edge or ā€˜leading edge’ technique vs. outer edge to outer edge), at the widest part of the skull, using an angle that is perpendicular to the midline falx (Figure 1)19. The same technique as that used to establish the reference chart should be used. The cephalic index is a ratio of the maximum head width to its maximum length and this value can be used to characterize fetal head shape. Abnormal head shape (e.g. brachycephaly and dolichocephaly) can be associated with syndromes. This finding can also lead to inaccurate estimates of fetal age when the BPD is used; in these cases, HC measurements are more reliable20. As described for the BPD, ensuring that the circumference placement markers correspond to the technique described on the reference chart. If the ultrasound equipment has ellipse measurement capacity, then the HC can be measured directly by placing the ellipse around the outside of the skull bone echoes (Figure 1). Alternatively, the HC can be calculated from the BPD and occipitofrontal diameter (OFD) as follows: the BPD is measured using a leading edge technique as described in the previous section whereas the OFD is obtained by placing the calipers in the middle of the bone echo at both the frontal and occipital skull bones. HC is then calculated using the equation: HC = 1.62Ɨ (BPD + OFD). - Transverse section of the fetal abdomen (as circular as possible); - umbilical vein at the level of the portal sinus; - stomach bubble visualized; - kidneys should not be visible. The AC is measured at the outer surface of the skin line, either directly with ellipse calipers or calculated from linear measurements made perpendicular to each other, usually the anteroposterior abdominal diameter (APAD) and transverse abdominal diameter (TAD) (Figure 1). To measure the APAD, the calipers are placed on the outer borders of the body outline, from the posterior aspect (skin covering the spine) to the anterior abdominal wall. To measure the TAD, the calipers are placed on the outer borders of the body outline, across the abdomen at the widest point. The AC is then calculated using the formula: AC = Ļ€ (APAD + TAD)/2 = 1.57 (APAD + TAD). The FDL is imaged optimally with both ends of the ossified metaphysis clearly visible21, 22. The longest axis of the ossified diaphysis is measured. The same technique as that used to establish the reference chart should be used with regard to the angle between the femur and the insonating ultrasound beams. An angle of insonation between 45° and 90° is typical. Each caliper is placed at the ends of the ossified diaphysis without including the distal femoral epiphysis if it is visible (Figure 1). This measurement should exclude triangular spur artifacts that can falsely extend the diaphysis length. Mid-trimester sonographic measurements can be used to identify abnormalities of fetal size23, 24. Some countries also use this information to estimate fetal weight as a baseline parameter for the detection of subsequent growth problems. Many ā€˜size discrepancies’ are explained by incorrect menstrual age estimates, even in women with ā€˜certain dates’25, 26. If gestational age is determined at an earlier scan, EFW can be compared to dedicated normal, preferably local, reference ranges for this parameter14, 27, 28. However, the degree of deviation from normal at this early stage of pregnancy that would justify action (e.g. follow-up scan to assess fetal growth or fetal chromosomal analysis) has not been firmly established. Amniotic fluid volume can be estimated subjectively or using sonographic measurements. Subjective estimation is not inferior to the quantitative measurement techniques (e.g. deepest pocket, amniotic fluid index) when performed by experienced examiners29, 30. Patients with deviations from normal should have more detailed anatomical evaluation and clinical follow-up. Normal fetuses typically have a relaxed position and show regular movements. There are no specific movement patterns at this stage of pregnancy. Temporary absence or reduction of fetal movements during the scan should not be considered as a risk factor31. Abnormal positioning or unusually restricted or persistently absent fetal movements may suggest abnormal fetal conditions such as arthrogryposis32. The biophysical profile is not considered part of a routine mid-trimester scan33. The application of Doppler techniques is not currently recommended as part of the routine second-trimester ultrasound examination. There is insufficient evidence to support universal use of uterine or umbilical artery Doppler evaluation for the screening of low-risk pregnancies34-36. - visualization of the placental cord insertion; - distinguishing features (gender, unique markers, position in uterus); - determination of chorionicity is sometimes feasible in the second trimester if there are clearly two separate placental masses and discordant genders. Chorionicity is much better evaluated before 14–15 weeks (lambda sign or T-sign). Follow-up of multiple pregnancies should be arranged in accordance with local guidelines and clinical practices. Recommended minimum requirements for a basic fetal anatomical survey during the mid-trimester of pregnancy are summarized in Table 1. - Size: measurements are performed as mentioned in the biometry section. - Shape: the skull normally has an oval shape without focal protrusions or defects and is interrupted only by narrow echolucent sutures. Alterations of shape (e.g. lemon, strawberry, cloverleaf) should be documented and investigated41. - Integrity: no bony defects should be present. Rarely, brain tissue can extrude through defects of the frontal or occipital bones, although cephaloceles may occur at other sites as well. - Density: normal skull density is manifested as a continuous echogenic structure that is interrupted only by cranial sutures in specific anatomical locations. The absence of this whiteness or extreme visibility of the fetal brain should raise suspicion of poor mineralization (e.g. osteogenesis imperfecta, hypophosphatasia)42. Poor mineralization is also suggested when the skull becomes easily depressed as a result of manual pressure from transducer placement against the maternal abdominal wall. Transverse views of the fetal head demonstrating standard transventricular (a), transthalamic (b) and transcerebellar (c) scanning planes. The first two planes allow assessment of the anatomical integrity of the brain. The third permits evaluation of the cerebellum and cisterna magna in the posterior fossa. - lateral ventricles (including choroid plexi); - cavum septi pellucidi; - midline falx; - thalami; - cerebellum; - cisterna magna. Minimum evaluation of the fetal face should include an attempt to visualize the upper lip for possible cleft lip anomaly43 (Figure 3a). If technically feasible, other facial features that can be assessed include the median facial profile (Figure 3b), orbits (Figure 3c), nose and nostrils. Ultrasound imaging of the fetal face. The mouth, lips and nose are typically evaluated in a coronal view (a). If technically feasible, a median facial profile provides important diagnostic clues for cleft lip, frontal bossing, micrognathia and nasal bone anomalies (b). Both fetal orbits should appear symmetrical and intact (c). The neck normally appears as cylindrical with no protuberances, masses or fluid collections44. Obvious neck masses such as cystic hygromas or teratomas should be documented. The shape should be regular with a smooth transition to the abdomen45. The ribs should have normal curvature without deformities. Both lungs should appear homogeneous and without evidence of mediastinal shift or masses. The diaphragmatic interface can often be visualized as a hypoechoic dividing line between the thoracic and abdominal content (e.g. liver and stomach)46, 47. The basic and extended basic cardiac ultrasonographic examinations are designed to maximize the detection of congenital heart disease during a second-trimester scan (Figure 4)48. A single acoustic focal zone and relatively narrow field of view can help to maximize frame rates. Images should be magnified until the heart fills at least a third to half of the display screen. Basic and extended basic views of the fetal heart. The basic cardiac scan is obtained from a four-chamber view (a) when both ventricles are seen during end diastole (calipers). An extended basic scan of the great arteries demonstrates the left (b) and right (c) ventricular outflow tracts. Separate arterial outflow tracts (calipers), approximately equal in size, exit their respective ventricles by crossing over each other in normal fetuses. The basic cardiac screening examination is interpreted from a four-chamber view of the fetal heart. A normal regular rate ranges from 120 to 160 beats per min. The heart should be located in the left chest (same side as the fetal stomach) if the situs is normal. A normal heart is usually no larger than one-third of the area of the chest and is without pericardial effusion. The heart is normally deviated by about 45 ± 20° (2 SD) towards the left side of the fetus49. An extended basic cardiac evaluation, which includes the aortic and pulmonary outflow tracts, can increase the detection rates for major cardiac malformations above those achievable by the four-chamber view alone. Views additional to those of the basic examination are more likely to identify conotruncal anomalies such as tetralogy of Fallot, transposition of the great arteries, double outlet right ventricle and truncus arteriosus. Normal great vessels are approximately equal in size and should cross each other as they exit from their respective ventricular chambers. Some investigators have described an optional ā€˜three-vessels and trachea view’ that may also be useful for evaluating the pulmonary artery, ascending aorta and right superior vena cava, in terms of their relative sizes and anatomical relationships50. For a more detailed description of fetal cardiac screening, the reader is referred to the ISUOG guidelines for the fetal cardiac examination. This document can be downloaded from the Society's website48 (http://www.isuog.org). Abdominal organ situs should be determined51. The fetal stomach should be identified in its normal position on the left side. Bowel should be contained within the abdomen and the umbilical cord should insert into an intact abdominal wall. Abnormal fluid collections of the bowel (e.g. enteric cysts, obvious bowel dilatation) should be documented. Aside from the left-sided stomach, a fetal gallbladder may be seen in the right upper quadrant next to the liver, although this latter finding is not a minimum requirement of the basic scan. Any other cystic structures seen in the abdomen should prompt referral for a more detailed scan. The fetal umbilical cord insertion (Figure 5a) site should be examined for evidence of a ventral wall defect such as omphalocele or gastroschisis. Cord vessels may also be counted using gray-scale imaging as an optional component of the routine anatomical survey. Ultrasound imaging of the fetal cord insertion site, bladder with umbilical arteries, kidneys and spine. The umbilical cord insertion site into the fetal abdomen (a, arrow) provides information about the presence of ventral wall defects such as omphalocele or gastroschisis. The fetal bladder (b, *) and both kidneys (c, arrowheads) should be identified. Axial and longitudinal views of the spine provide effective screening for spina bifida, especially when these scanning planes are abnormal in the presence of frontal skull deformation and an obliterated cisterna magna (c,d). The fetal bladder and both kidneys should be identified (Figures 5b and 5c). If either bladder or renal pelves appears enlarged, a measurement should be documented. Persistent failure to visualize the bladder should prompt referral for a more detailed assessment. A satisfactory examination of the fetal spine requires expertise and meticulous scanning, and the results are heavily dependent upon fetal position (Figures 5c and 5d). Complete evaluation of the fetal spine from every projection is not part of the basic examination, although transverse and sagittal views are usually informative. The most frequent of the severe spinal abnormalities, open spina bifida, is usually associated with abnormal intracranial anatomy such as a characteristic cerebellar deformity (banana sign) and obliterated cisterna magna. Other views of the fetal spine may identify other spinal malformations, including vertebral abnormalities and sacral agenesis19. The presence or absence of both arms/hands (Figure 6a) and both legs/feet (Figure 6b) should be documented using a systematic approach52. Counting fingers or toes is not required as part of the routine mid-trimester scan. Sonography of the fetal upper extremities, lower extremities and placenta. The presence or absence of the upper and lower limbs should be documented routinely unless they are poorly visualized due to technical factors (a, b). Placental position should be determined in relation to the maternal cervix (c). During ultrasonography, the placental location (Figure 6c), its relationship with the internal cervical os and its appearance should be described. Examples of abnormal placental findings include the presence of hemorrhage, multiple cysts with triploidy and placental masses such as chorioangioma. In most cases of the routine second-trimester examination, transabdominal ultrasonography permits clear definition of the relationship between placenta and internal cervical os. If the lower placental edge reaches or overlaps the internal os, a follow-up examination in the third trimester is recommended53, 54. Women with a history of uterine surgery and low anterior placenta or placenta previa are at risk for placental attachment disorders. In these cases, the placenta should be examined for findings of accreta, the most sensitive of which are the presence of multiple irregular placental lacunae that show arterial or mixed flow55, 56. Abnormal appearance of the uterine wall–bladder wall interface is quite specific for accreta, but is seen in few cases. Loss of the echolucent space between an anterior placenta and the uterine wall is neither a sensitive nor a specific marker for placenta accreta. Although placenta accreta may be suspected during a routine mid-trimester scan, a more detailed evaluation is usually required to further examine this possibility. Characterization of external genitalia to determine fetal gender is not considered mandatory in the context of a mid-trimester routine scan. Reporting of gender should be considered only with parental consent and in the context of local practices. Several studies have demonstrated a strong correlation between short cervical length on transvaginal scan and subsequent preterm birth. However, several randomized controlled trials that examined the combination of routine cervical length measurement and subsequent interventions (cerclage, progesterone) failed to demonstrate conclusively any cost-effectiveness of such screening programs57, 58. Currently, there is insufficient evidence to recommend routine cervical length measurements at the mid trimester in an unselected population59. Identification of women with short cervical length may have significant benefits for research purposes and further intervention studies, but this is not a justification for routine cervical scanning. Such a universal screening program would not only require significant resources and quality assurance, but also cause potential disadvantages by introducing anxiety and unnecessary intervention. Uterine fibroids and adnexal masses should be documented if they are likely to interfere with labor60. These guidelines were developed by the Prenatal Ultrasound Screening Task Force under the auspices of the ISUOG Clinical Standards Committee; Chair, Dr Wesley Lee, Department of Obstetrics and Gynecology, Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA Appreciation is particularly extended to specialty consultants who contributed to this project: Task Force Chair: Laurent J Salomon, MD, PhD HĆ“pital Necker Enfants Malades, AP-HP, UniversitĆ© Paris Descartes, Paris, France Zarko Alfirevic, MD Division of Perinatal and Reproductive Medicine, University of Liverpool, Liverpool Women's Hospital, Liverpool, UK Vincenzo Berghella, MD Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, PA, USA Caterina Bilardo, MD Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands Edgar Hernandez-Andrade, MD Department of Maternal Fetal Medicine, National Institute of Perinatal Medicine, Mexico City, Mexico Synnove Lian Johnsen, MD Haukeland University Hospital, Bergen, Norway Karim Kalache, MD Department of Obstetrics, CharitĆ© University Hospital-Campus Mitte, Berlin, Germany Wesley Lee, MD Division of Fetal Imaging, William Beaumont Hospital, Royal Oak, MI, USA Kwok Yin Leung, MD Department of Obstetrics and Gynecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China Gustavo Malinger, MD Fetal Neurology Clinic, Department of Obstetrics and Gynecology, Wolfson Medical Center, Tel-Aviv University, Israel Hernan Munoz, MD Department of Obstetrics and Gynecology, Universidad de Chile, Clinica Las Condes, Santiago, Chile Federico Prefumo, MD, PhD Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy Ants Toi, MD Mount Sinai Hospital, Department of Medical Imaging, University of Toronto, Toronto, Canada Special appreciation to Jacques Abramowicz (USA), MD, PhD, for his contribution to the Safety section and to Jean-Philippe Bault (France), MD, for providing some of the images. Copies of this document are available at: http://www.isuog.org ISUOG Secretariat Unit 4, Blythe Mews Blythe Road London W14 0HW, UK e-mail: [email protected]
Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first … Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations.In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Down's syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13.Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001).In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).
Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental … Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis.
We have developed an in vitro method for amplifying a large fraction of the DNA sequences present in a single haploid cell by repeated primer extensions using a mixture of … We have developed an in vitro method for amplifying a large fraction of the DNA sequences present in a single haploid cell by repeated primer extensions using a mixture of 15-base random oligonucleotides. We studied 12 genetic loci and estimate that the probability of amplifying any sequence in the genome to a minimum of 30 copies is not less than 0.78 (95% confidence). Whole genome amplification beginning with a single cell, or other samples with very small amounts of DNA, has significant implications for multipoint mapping by sperm or oocyte typing and possibly for genetic disease diagnosis, forensics, and the analysis of ancient DNA samples.
Pregnancy rates in women of advanced maternal age undergoing in vitro fertilization (IVF) are disappointingly low. It has been suggested that the use of preimplantation genetic screening of cleavage-stage embryos … Pregnancy rates in women of advanced maternal age undergoing in vitro fertilization (IVF) are disappointingly low. It has been suggested that the use of preimplantation genetic screening of cleavage-stage embryos for aneuploidies may improve the effectiveness of IVF in these women.We conducted a multicenter, randomized, double-blind, controlled trial comparing three cycles of IVF with and without preimplantation genetic screening in women 35 through 41 years of age. The primary outcome measure was ongoing pregnancy at 12 weeks of gestation. The secondary outcome measures were biochemical pregnancy, clinical pregnancy, miscarriage, and live birth.Four hundred eight women (206 assigned to preimplantation genetic screening and 202 assigned to the control group) underwent 836 cycles of IVF (434 cycles with and 402 cycles without preimplantation genetic screening). The ongoing-pregnancy rate was significantly lower in the women assigned to preimplantation genetic screening (52 of 206 women [25%]) than in those not assigned to preimplantation genetic screening (74 of 202 women [37%]; rate ratio, 0.69; 95% confidence interval [CI], 0.51 to 0.93). The women assigned to preimplantation genetic screening also had a significantly lower live-birth rate (49 of 206 women [24%] vs. 71 of 202 women [35%]; rate ratio, 0.68; 95% CI, 0.50 to 0.92).Preimplantation genetic screening did not increase but instead significantly reduced the rates of ongoing pregnancies and live births after IVF in women of advanced maternal age. (Current Controlled Trials number, ISRCTN76355836 [controlled-trials.com].).
Chromosomal aneuploidy is the major reason why couples opt for prenatal diagnosis. Current methods for definitive diagnosis rely on invasive procedures, such as chorionic villus sampling and amniocentesis, and are … Chromosomal aneuploidy is the major reason why couples opt for prenatal diagnosis. Current methods for definitive diagnosis rely on invasive procedures, such as chorionic villus sampling and amniocentesis, and are associated with a risk of fetal miscarriage. Fetal DNA has been found in maternal plasma but exists as a minor fraction among a high background of maternal DNA. Hence, quantitative perturbations caused by an aneuploid chromosome in the fetal genome to the overall representation of sequences from that chromosome in maternal plasma would be small. Even with highly precise single molecule counting methods such as digital PCR, a large number of DNA molecules and hence maternal plasma volume would need to be analyzed to achieve the necessary analytical precision. Here we reasoned that instead of using approaches that target specific gene loci, the use of a locus-independent method would greatly increase the number of target molecules from the aneuploid chromosome that could be analyzed within the same fixed volume of plasma. Hence, we used massively parallel genomic sequencing to quantify maternal plasma DNA sequences for the noninvasive prenatal detection of fetal trisomy 21. Twenty-eight first and second trimester maternal plasma samples were tested. All 14 trisomy 21 fetuses and 14 euploid fetuses were correctly identified. Massively parallel plasma DNA sequencing represents a new approach that is potentially applicable to all pregnancies for the noninvasive prenatal diagnosis of fetal chromosomal aneuploidies.
Epidemiologic studies, retrospective and prospective, were done on 1500 abortions collected from 1966-1972. No secular or seasonal variations were observed. From the analysis of the relative frequencies of the different … Epidemiologic studies, retrospective and prospective, were done on 1500 abortions collected from 1966-1972. No secular or seasonal variations were observed. From the analysis of the relative frequencies of the different types of chromsome anomalies it is estimated that 1 out of every 2 conceptions has a chromosome anomaly. Maternal-age influence was found only for the autosomal trisomy group, mainly D and G trisomies. No effect of oral contraceptives were discovered. An increased frequency of chromosome anomalies occurred after ovulation-inducing therapy and after occupational exposure of the father to irradiation. No variations in the fertility rate and in the frequency of congenital malformations in births following abortions was noted. The incidence of recurring abortion was mainly influenced by the reproductive history of the couple before the karyotyped abortion.
To validate the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or … To validate the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or chorionic villus sampling.Diagnostic accuracy validated against full karyotyping, using prospectively collected or archived maternal plasma samples.Prenatal diagnostic units in Hong Kong, United Kingdom, and the Netherlands.753 pregnant women at high risk for fetal trisomy 21 who underwent definitive diagnosis by full karyotyping, of whom 86 had a fetus with trisomy 21. Intervention Multiplexed massively parallel sequencing of DNA molecules in maternal plasma according to two protocols with different levels of sample throughput: 2-plex and 8-plex sequencing.Proportion of DNA molecules that originated from chromosome 21. A trisomy 21 fetus was diagnosed when the z score for the proportion of chromosome 21 DNA molecules was >3. Diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were calculated for trisomy 21 detection.Results were available from 753 pregnancies with the 8-plex sequencing protocol and from 314 pregnancies with the 2-plex protocol. The performance of the 2-plex protocol was superior to that of the 8-plex protocol. With the 2-plex protocol, trisomy 21 fetuses were detected at 100% sensitivity and 97.9% specificity, which resulted in a positive predictive value of 96.6% and negative predictive value of 100%. The 8-plex protocol detected 79.1% of the trisomy 21 fetuses and 98.9% specificity, giving a positive predictive value of 91.9% and negative predictive value of 96.9%.Multiplexed maternal plasma DNA sequencing analysis could be used to rule out fetal trisomy 21 among high risk pregnancies. If referrals for amniocentesis or chorionic villus sampling were based on the sequencing test results, about 98% of the invasive diagnostic procedures could be avoided.
Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement.A blinded, nested … Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement.A blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequencing in 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory.Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alternative interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance.When applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis.
The ability to determine fetal RhD status noninvasively is useful in the treatment of RhD-sensitized pregnant women whose partners are heterozygous for the RhD gene. The recent demonstration of fetal … The ability to determine fetal RhD status noninvasively is useful in the treatment of RhD-sensitized pregnant women whose partners are heterozygous for the RhD gene. The recent demonstration of fetal DNA in maternal plasma raises the possibility that fetal RhD genotyping may be possible with the use of maternal plasma.
Advancing technology has made detecting fetal abnormalities in the first and second trimesters a reality. Few families are prepared for the difficult decisions that must be made if their unborn … Advancing technology has made detecting fetal abnormalities in the first and second trimesters a reality. Few families are prepared for the difficult decisions that must be made if their unborn children are diagnosed with a life-limiting condition. Expectant parents are compelled to make decisions on the basis of limited options. A systematic review of the literature is presented with an aim to inform clinicians of parental experiences and outcomes after diagnosis of a fetal anomaly. The review focused on patients given a diagnosis for fetal anomalies for the 40-year period from 1970 to 2010 by using the key words such as fetal anomaly, congenital malformations, pregnancy termination, perinatal palliative care, and perinatal hospice. Regardless of the option taken, women often experienced intense grief reactions. Both giving birth to a child with a life-limiting condition and termination of pregnancy for fetal anomaly can be emotionally traumatic life events, both associated with psychological morbidity. Nonaggressive obstetric management, allowing natural birth without life-sustaining therapeutics, is an option for families. Couples presented with a coordinated perinatal palliative care model may opt to continue their pregnancy. Families who experienced perinatal hospice/palliative care report positive feedback, but more research is needed to explore the psychological outcomes of this choice.
This review of genomic perinatal opportunities and uses will provide counselling and personal genetic knowledge for improved patient care. M/M: This focused systematic analysis and review has used PUBMED keywords … This review of genomic perinatal opportunities and uses will provide counselling and personal genetic knowledge for improved patient care. M/M: This focused systematic analysis and review has used PUBMED keywords to identify genomic testing for ultrasound identified fetal anomaly (ies) that require diagnostic testing after an informed consent process. Multiple fetal anomalies, using TRIO sequencing processes, have a better diagnostic yield, with certain cohorts > 50%. For the single anatomic categories, skeletal, central nervous system, and renal systems, using WES fetal sequencing (most commonly) for a diagnostic result, have the larger incremental diagnostic yield over CMA. The phenotype-genotype (fetal-genomic result) consideration and use of the pES technology can be summarized using a SWOT analysis: strength (enhanced evaluation of fetal-neonatal genomic abnormalities not identified by standard chromosomal microarray and improved ethical care decisions); weakness (the understanding and complexity of genomic pathology and testing / the fiscal cost for professional time and the health system services); opportunity (an increased recognition of fetal genetic risk pathology [de novo or inherited carrier mutations] with improved understanding and knowledge translation of counselling for recurrence risk); threat (inability to provide a genetic diagnosis or interpret a variant of unknown significance or the discovery of incidental findings or unanticipated parental genomic diagnoses).
ABSTRACT Objective To analyze the ultrasound findings, single nucleotide polymorphism microarray (SNP array) results, pregnancy outcomes, and follow‐up information of fetuses with 16p13.11 deletion or duplication. Methods This retrospective study … ABSTRACT Objective To analyze the ultrasound findings, single nucleotide polymorphism microarray (SNP array) results, pregnancy outcomes, and follow‐up information of fetuses with 16p13.11 deletion or duplication. Methods This retrospective study collected data from 14 fetuses diagnosed with 16p13.11 deletion and 12 fetuses with 16p13.11 duplication. The study involved a review and analysis of maternal demographics, ultrasound findings, SNP‐array results, pregnancy outcomes, and follow‐up information. Results The copy number variations (CNVs) observed ranged in size from 0.92 to 2.85 Mb for 16p13.11 deletions and from 0.89 to 2.84 Mb for duplications. These CNVs included seven OMIM genes: NDE1 , MYH11 , ABCC1 , XYLT1 , MARF1 , CEP20 , and ABCC6 . Among the 14 fetuses with 16p13.11 deletions, seven (50.0%, 7/14) revealed abnormalities in ultrasound findings. Cardiovascular anomalies were present in five cases (35.7%, 5/14); two cases (14.3%, 2/14) showed lateral ventricular widening. Cases 2 and 14 were particularly noteworthy, as both presented complex malformations affecting multiple organs. Among the 12 fetuses with duplications, five cases (41.7%, 5/12) exhibited ultrasound abnormalities. Of these, three cases (25.0%, 3/12) presented with cardiovascular abnormalities; two cases (16.7%, 2/12) displayed widened lateral ventricles. Case 25 was particularly distinct, featuring complex multiorgan malformations that included widened lateral ventricles, tricuspid regurgitation, and a right ear malformation. Of the eight fetuses with 16p13.11 deletions whose pregnancies were continued, three exhibited neurodevelopmental abnormalities. Ten fetuses with 16p13.11 duplications that were followed up, two cases showed neurodevelopmental abnormalities. Conclusion Our study expanded the clinical phenotype spectrum of fetuses with 16p13.11 deletion and duplication and conducted a preliminary evaluation of prenatal ultrasound findings in conjunction with postnatal clinical phenotypes. The primary manifestations observed in fetuses with 16p13.11 deletion and duplication are likely to be cardiovascular malformations and widened lateral ventricles.
To evaluate the incidence, prenatal findings, and pregnancy outcomes of rare autosomal trisomies (RATs). This retrospective cohort study included cases diagnosed via chorionic villus sampling, amniocentesis, or fetal cord blood … To evaluate the incidence, prenatal findings, and pregnancy outcomes of rare autosomal trisomies (RATs). This retrospective cohort study included cases diagnosed via chorionic villus sampling, amniocentesis, or fetal cord blood sampling. Data collected included maternal demographics, gestational age, first-trimester screening results, ultrasound findings, genetic analyses, and pregnancy outcomes. A total of 354 cases of common trisomies and 18 cases of RATs (trisomies 2, 5, 7, 8, 9, 12, 20, and 22) were identified. Common trisomies were associated with higher maternal age (p = 0.003) and advanced maternal age rates (≄35 years) (p = 0.009). Fetal (61.1% vs. 1.7%) and confined placental mosaicism (22.2% vs. 0.3%) were significantly more frequent in RATs (p < 0.001, for all). Ultrasound anomalies were observed in 11 of 18 (61.1%) RATs, with trisomy 22 frequently involving craniofacial and cardiac abnormalities. RATs display diverse clinical outcomes. Mosaicism and ultrasound findings are critical for assessing prognosis and guiding clinical management.
ABSTRACT Objective To assess parental preferences, expectations and understanding of genome‐wide cell‐free DNA screening (gwNIPT) in Australia. Method A cross‐sectional survey study utilizing an anonymous electronic questionnaire was conducted across … ABSTRACT Objective To assess parental preferences, expectations and understanding of genome‐wide cell‐free DNA screening (gwNIPT) in Australia. Method A cross‐sectional survey study utilizing an anonymous electronic questionnaire was conducted across three participating screening services in Australia between September 2023 and November 2024. Questions pertained to respondent demographics, pre‐screening counselling, and accuracy expectations of gwNIPT for various chromosomal anomalies. Statistical analyses to investigate associations between responses used Chi‐squared and Fisher's exact tests, ordinal logistic regression, and the Kruskal‐Wallis test. Results There were 329 survey responses recorded, of which 216 were completed (65.7%). The most frequent source of NIPT referral was a medical doctor (74.1%), and the most common duration of pre‐screening counselling was 5 minutes (41.0%). Respondents showed overwhelming interest in all anomalies included in gwNIPT as well as various phenotypic outcomes including those of uncertain clinical significance. Despite this, only a minority of patients were aware that they were undergoing genome‐wide screening (38.2%), and respondents did not anticipate a statistically significant difference in screening accuracy across different anomaly types ( p = 0.715). Conclusion Respondents undergoing gwNIPT indicated a preference to receive as much genetic information about their pregnancies as possible. Pre‐screening counselling should therefore include the limitations of gwNIPT.
Objective To evaluate the performance and screening value of noninvasive prenatal testing (NIPT) in low-risk pregnancies. Methods A retrospective analysis was conducted on 60193 low-risk pregnancies over the last 5 … Objective To evaluate the performance and screening value of noninvasive prenatal testing (NIPT) in low-risk pregnancies. Methods A retrospective analysis was conducted on 60193 low-risk pregnancies over the last 5 years. Whole-genome sequencing of maternal plasma cell-free DNA was performed using next-generation sequencing. NIPT-positive results were confirmed using amniocentesis with karyotyping and/or copy number variation sequencing and chromosomal microarray analysis. Fetal outcomes were assessed using electronic medical records or telephone calls. Results Overall, 598 (0.99%) NIPT-positive cases were identified. The distribution of chromosomal abnormalities included sex chromosome aneuploidies (SCAs; 55.85%), rare autosomal aneuploidies (RAAs; 20.40%), copy number variations (CNVs; 11.20%), trisomy 21 (T21; 6.86%), trisomy 13 (T13; 4.01%), and trisomy 18 (T18; 1.67%). A total of 572 (95.65%) patients with NIPT-positive results underwent amniocentesis, and 55.77% (319/572) cases were confirmed. The positive predictive values (PPV) for T21, T18, T13, SCAs, RAAs, and CNVs were 87.50%, 60.00%, 34.78%, 58.97%, 32.50%, and 69.70%, respectively, and the PPV for the trisomy was higher than that for the X-monomer in SCAs. NIPT-positive results for RAAs were common in T8, T10, T16 and T20, but T16 was the most common true positive result, accounting for 33.33% (13/39) of the cases. The termination rates of true-positive pregnancies were 100% (T21, T18 and T13), 79.49% (RAAs), 67.39% (CNVs) and 78.07% (SCAs). Conclusion This study highlights the importance of genome-wide screening based on NIPT in low-risk pregnancies. Prenatal screening by NIPT has a high sensitivity and PPV. Moreover, it can greatly reduce invasive procedures and birth defects.
ABSTRACT Objective The discovery of fetal cell‐free DNA (cfDNA) has revolutionized prenatal diagnostics through non‐invasive prenatal testing (NIPT), which depends on accurately measuring the fetal fraction (FF) in maternal plasma. … ABSTRACT Objective The discovery of fetal cell‐free DNA (cfDNA) has revolutionized prenatal diagnostics through non‐invasive prenatal testing (NIPT), which depends on accurately measuring the fetal fraction (FF) in maternal plasma. While FF is known to be influenced by maternal and fetal factors, the impact of intraday rhythms remains unclear. This study investigated whether FF varies based on blood draw timing. Methods Data from 2519 euploid singleton pregnancies undergoing NIPT were analyzed. Key variables included maternal age, BMI, gestational age, fetal sex, and blood draw timing (06:50–21:00). FF was measured using the Harmony Prenatal IVD Test. Multiple linear regression identified independent predictors of FF, while intraday variation was assessed using Mann‐Whitney U tests and boxplots. Results FF showed a significant positive relationship with blood draw timing ( β = 0.00176 per hour, p &lt; 0.005), with afternoon values approximately 10% higher than morning values (∼0.01 difference). Other predictors included BMI (negative), gestational age (positive), and fetal sex (higher in females). Blood draw timing appeared to be a stronger predictor of FF than gestational age or fetal sex, second only to BMI. Conclusion This novel finding demonstrates diurnal variation in FF, suggesting that optimizing blood draw timing could improve NIPT accuracy, particularly in borderline cases. Further research is needed to confirm the clinical implications.
Abstract Background Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and … Abstract Background Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and are associated with a wide range of developmental, cognitive, and physical health outcomes. While clinical research on SCAs has expanded over the past two decades, it is unclear whether the populations included in these studies reflect the demographic diversity of those affected. Assessing representation is critical to ensuring research findings are generalizable and applicable to diverse patient populations. Methods We conducted a systematic review of global clinical research on SCAs published in English between January 2004 and May 2024. Searches were performed in Ovid MEDLINEĀ® ALL, Embase, and Web of Science. Studies were included if they enrolled ≄10 participants and excluded if they were case reports, reviews, or meta-analyses. We extracted data from 1,474 studies on geographic location, participant karyotypes, and demographic metrics, including race, ethnicity, and socioeconomic status (SES) reported. Trends in demographic reporting were examined over time and by geographic region. For U.S.-based studies reporting race/ethnicity, we compared pooled participant demographics to national census data. Results SCA research is concentrated within a small number of geographic areas, primarily in Europe (51.4%) and the U.S. (23.6%). Reporting rates of race or ethnicity for U.S. papers increased over the 20-year observation period, with an average increase of 1.5% ± 0.4% per year (p = 0.003), peaking in 2024 with 61.4% of U.S.-based papers presenting demographics. When reported, studies consistently overrepresented non-Hispanic White (p&lt;0.001) and college-educated (p&lt;0.001) participants relative to U.S. census benchmarks. Conclusions This systematic review reveals persistent gaps in the demographic reporting and representation of participants in SCA research. Even in the U.S., where population diversity is high, published studies do not reflect the expected racial, ethnic, and socioeconomic makeup of affected individuals. To ensure that research findings are equitable and clinically relevant, future studies should adopt standardized demographic reporting and prioritize inclusive enrollment strategies to reflect the full spectrum of individuals with SCAs.
INTRODUƇƃO: As gestaƧƵes gemelares podem ser classificados como monocoriĆ“nicas (placenta Ćŗnica) ou dicoriĆ“nicas (placentas separadas). GestaƧƵes gemelares monocoriĆ“nicas representam um subgrupo de alto risco obstĆ©trico, caracterizadas por maiores taxas de … INTRODUƇƃO: As gestaƧƵes gemelares podem ser classificados como monocoriĆ“nicas (placenta Ćŗnica) ou dicoriĆ“nicas (placentas separadas). GestaƧƵes gemelares monocoriĆ“nicas representam um subgrupo de alto risco obstĆ©trico, caracterizadas por maiores taxas de morbimortalidade fetal e neonatal. ComplicaƧƵes como a sĆ­ndrome de transfusĆ£o feto-fetal (STFF), restrição do crescimento seletivo (CIUR) e malformaƧƵes congĆŖnitas sĆ£o mais prevalentes. O diagnóstico precoce e o manejo especializado sĆ£o essenciais para melhorar os desfechos. OBJETIVO: Avaliar os desfechos gestacionais, fetais e neonatais de gestaƧƵes gemelares monocoriĆ“nicas acompanhadas em um serviƧo de referĆŖncia em medicina fetal no sul do Brasil, focando na identificação de complicaƧƵes e na anĆ”lise das intervenƧƵes terapĆŖuticas realizadas. MƉTODO: Estudo de coorte retrospectivo com 80 pacientes diagnosticadas com gestação gemelar monocoriĆ“nica, acompanhadas entre 2017 e 2024. Foram coletadas variĆ”veis maternas, fetais e neonatais. As anĆ”lises estatĆ­sticas foram realizadas com o SPSS 22.0, com significĆ¢ncia de p&lt;0,05. RESULTADOS: A maioria das pacientes (75%) foi encaminhada via sistema de regulação. A mĆ©dia de idade gestacional no inĆ­cio do prĆ©-natal foi de 21 semanas. Ocorreram 16 casos de CIUR, 12 de STFF, um caso de sequĆŖncia anemia-policitemia e outro de gĆŖmeo acĆ”rdico. A intervenção com fetoscopia a laser foi realizada em seis casos de STFF. A mortalidade total foi de 16%, e 65% dos recĆ©m-nascidos necessitaram de suporte intensivo neonatal. Sete casos de malformaƧƵes congĆŖnitas resultaram em óbito fetal ou neonatal. DISCUSSƃO: As taxas de complicaƧƵes e mortalidade foram superiores Ć s descritas na literatura, possivelmente devido ao perfil de complexidade do serviƧo e ao acesso tardio a tecnologias como a fetoscopia. A intervenção com laser demonstrou efetividade, com maior taxa de sobrevivĆŖncia entre os gĆŖmeos. CONCLUSƃO: O manejo das gestaƧƵes monocoriĆ“nicas exige diagnóstico precoce da corionicidade, acompanhamento rigoroso com ultrassonografia seriada, e acesso a terapias invasivas como a fetoscopia. Ɖ imprescindĆ­vel a existĆŖncia de serviƧos estruturados de medicina fetal, aliados ao suporte de UTIs neonatais para reduzir a mortalidade.
O objetivo deste estudo foi avaliar se os resultados de gravidez diferem entre transferĆŖncias de blastocistos Ćŗnicos vitrificados-descongelados no 5Āŗ e 6Āŗ dia em ciclos de reposição hormonal sem o … O objetivo deste estudo foi avaliar se os resultados de gravidez diferem entre transferĆŖncias de blastocistos Ćŗnicos vitrificados-descongelados no 5Āŗ e 6Āŗ dia em ciclos de reposição hormonal sem o uso de teste genĆ©tico prĆ©-implantacional (PGT). Foi realizado um estudo de coorte retrospectivo entre 2022 e 2023 com 108 transferĆŖncias, sendo 64 no 5Āŗ dia e 44 no 6Āŗ dia. Participaram mulheres com menos de 42 anos submetidas Ć  injeção intracitoplasmĆ”tica de espermatozoides (ICSI), com exclusĆ£o de ciclos envolvendo doação de óvulos, mĆŗltiplas transferĆŖncias, preparo endometrial natural ou PGT. NĆ£o houve diferenƧas significativas nas taxas de gravidez (44% vs. 45%, p = 1), gravidez clĆ­nica (41% vs. 41%, p = 1), nascimento vivo (39% vs. 34%, p = 0,687) ou aborto (11% vs. 25%, p = 0,267). Os resultados sugerem que, em ciclos sem PGT com preparo endometrial controlado, os blastocistos do 6Āŗ dia apresentam desfechos clĆ­nicos semelhantes aos do 5Āŗ dia, o que pode trazer seguranƧa para clĆ­nicas e pacientes.
ABSTRACT Objectives International societies recommend amniocentesis (AC) after high‐risk non‐invasive prenatal testing (NIPT) because of potential inconclusive results from chorionic villus sampling (CVS) caused by placental mosaicism. Our study aimed … ABSTRACT Objectives International societies recommend amniocentesis (AC) after high‐risk non‐invasive prenatal testing (NIPT) because of potential inconclusive results from chorionic villus sampling (CVS) caused by placental mosaicism. Our study aimed to evaluate the necessity of confirmatory amniocentesis following CVS for trisomies 21, 18, and 13 with separate analysis of cytotrophoblast (CTB) and mesenchymal core (MC). Methods We retrospectively analyzed the confirmatory cytogenetic results between April 2017 and December 2022. CTB and MC were separated and analyzed by QF‐PCR and/or SNP array, and karyotyping when needed. Results Among 338 cases, 70% (237/339) of women underwent CVS (70.5%) and 30% (101/338) underwent AC. Mosaic trisomy in MC requiring additional amniocentesis was detected in 13.5% (5/37) of cases referred due to trisomy 13, 2.5% (4/158) of cases of trisomy 21% and 0% (0/42) of cases of trisomy 18. Conclusions A definitive diagnosis of CVS was achieved in 97.5%, 100%, and 86.5% of patients with high‐risk NIPT results for trisomy 21, 18, and 13, respectively. Moreover, our clinical practice confirms that the majority of pregnant women (70%) opted for CVS as a quick confirmatory test. We conclude that both CVS and AC can be offered when preceded by pre‐test counseling on the risks of potential inconclusive results as calculated in this study.
Background The aim of the present study was to investigate whether the CGG repeat length and AGG interruption patterns on the FMR1 gene affect female fecundity. Methods A total of … Background The aim of the present study was to investigate whether the CGG repeat length and AGG interruption patterns on the FMR1 gene affect female fecundity. Methods A total of 266 infertile patients and 276 fertile controls were included in the study. All participants received FMR1 testing using triplet repeat primed PCR and capillary electrophoresis. The allele with the smaller number of CGG repeats was defined as "allele 1", and the allele with the larger number of CGG repeats was defined as "allele 2". Results The mean number of CGG repeat length at allele 2 in the secondary infertility group was higher than that in the control group (33.1 ± 6.7 vs 30.9 ± 3.3, Bonferroni corrected p=0.003). The proportion of 35–44 CGG repeat at both FMR1 alleles showed a higher trend in the secondary infertility group as compared to the control group after adjusting for age, education, smoking status, cohort and the CGG repeats of the other FMR1 allele (aOR=7.812, 95% CI 0.884-69.001; p=0.064 for allele 1; aOR=3.657, 95% CI 2.193-6.098; p&amp;lt;0.001 for allele 2, respectively). Lower AMH levels were associated with increased CGG repeat length at allele 1 in infertile patients (Adjusted R 2 = 0.178, p=0.003) after adjusting for age, education, smoking status, infertility type and the CGG repeats of FMR1 allele 2. However, no significant correlation was found between the number of CGG repeats at allele 2 and AMH levels (Adjusted R 2 = 0.150, p=0.086). Although the difference was not statistically significant, there was a higher proportion of 3 AGG interruptions at both alleles in the secondary infertility group as compared to the control group (6.1% vs 0%, p=0.146 for allele 1, 30.6% vs 11.3%, p=0.099 for allele 2). Patients with 35–44 CGG repeat length showed a higher carrier rate of 3 AGG interruptions at both alleles (p&amp;lt;0.001 for both). Conclusions Overall, the high normal sized (35–44 CGG) repeat length at both FMR1 alleles may serve a promoting role in the development of secondary infertility in Asian women. In addition, the CGG repeat length at allele 1 appears to have a mild correlation with AMH levels in infertile patients.
Ana Carocha , Marƭa Ɓngeles Vicente , Joana Bernardeco +3 more | Best Practice & Research Clinical Obstetrics & Gynaecology
The second-trimester ultrasound is a crucial tool in prenatal care, typically conducted between 18 and 24 weeks of gestation to evaluate fetal anatomy, growth, and mid-trimester screening. This article provides … The second-trimester ultrasound is a crucial tool in prenatal care, typically conducted between 18 and 24 weeks of gestation to evaluate fetal anatomy, growth, and mid-trimester screening. This article provides a comprehensive overview of the best practices and guidelines for performing this examination, with a focus on detecting fetal anomalies. The ultrasound assesses key structures and evaluates fetal growth by measuring biometric parameters, which are essential for estimating fetal weight. Additionally, the article discusses the importance of placental evaluation, amniotic fluid levels measurement, and the risk of preterm birth through cervical length measurements. Factors that can affect the accuracy of the scan, such as the skill of the operator, the quality of the equipment, and maternal conditions such as obesity, are discussed. The article also addresses the limitations of the procedure, including variability in detection. Despite these challenges, the second-trimester ultrasound remains a valuable screening and diagnostic tool, providing essential information for managing pregnancies, especially in high-risk cases. Future directions include improving imaging technology, integrating artificial intelligence for anomaly detection, and standardizing ultrasound protocols to enhance diagnostic accuracy and ensure consistent prenatal care.
ABSTRACT Objective Nuchal translucency (NT) has been the mainstay of the first‐trimester screening assessment for fetal aneuploidies. Although NT is typically measured between 11 and 14 weeks' gestation when fetal … ABSTRACT Objective Nuchal translucency (NT) has been the mainstay of the first‐trimester screening assessment for fetal aneuploidies. Although NT is typically measured between 11 and 14 weeks' gestation when fetal crown–rump length (CRL) is between 45 and 85 mm, recent studies suggest that fetuses with increased NT measured in the early first trimester of pregnancy are also at high risk of aneuploidy, genetic disorders or adverse pregnancy outcomes. The aim of this systematic review was to report the outcomes of fetuses with early increased NT before 11 weeks' gestation. Methods MEDLINE, EMBASE and Cochrane databases were searched from inception to August 2024. The inclusion criteria were studies reporting the outcome of fetuses with increased NT, defined according to an absolute cut‐off or percentile in the original publication, and a CRL &lt; 45 mm. The primary outcome was a composite score of adverse pregnancy outcome, including the presence of either chromosomal, genetic or structural anomalies, or perinatal loss. The secondary outcomes explored were: resolution of increased NT at the 11–14‐week scan; chromosomal anomaly; copy‐number variant detected on chromosomal microarray; single‐gene disorder detected on next‐generation sequencing; structural anomaly; perinatal loss, defined as the occurrence of miscarriage or fetal loss; and termination of pregnancy. All outcomes were explored in the overall population of fetuses with early increased NT, according to the resolution or persistence of increased NT and according to different NT thickness (2.5–3.4 mm, 3.5–4.4 mm and ≄ 4.5 mm). Random effects meta‐analysis of proportions was used to combine the data and results were reported as pooled proportions with 95% CI. Results Five studies (401 fetuses with CRL &lt; 45 mm presenting with increased NT) were included in the systematic review and three of these (269 fetuses) were included in the meta‐analysis. Composite adverse pregnancy outcome complicated 42.0% (95% CI, 18.5–67.6%) of pregnancies presenting with early increased NT. Chromosomal or genetic anomaly at either pre‐ or postnatal assessment was reported in 40.2% (95% CI, 12.8–71.5%) of cases. Structural anomaly was identified on ultrasound in 5.9% (95% CI, 3.4–9.1%) of fetuses with early increased NT, and perinatal loss occurred in 9.7% (95% CI, 6.4–13.5%) of cases. Of the fetuses presenting with increased NT in the early first trimester of pregnancy, 48.8% (95% CI, 30.6–67.1%) showed resolution of the increased NT at the 11–14‐week scan, and the increased NT persisted in 51.2% (95% CI, 32.9–69.4%). Composite adverse pregnancy outcome occurred in 64.2% (95% CI, 51.8–75.6%) of fetuses in which increased NT was persistent at the 11–14‐week scan and in 19.4% (95% CI, 8.8–33.0%) of those in which the increased NT resolved. Finally, when considering different cut‐offs of NT thickness, adverse pregnancy outcome occurred in 31.9% (95% CI, 14.4–52.6%) of fetuses with NT between 2.5 and 3.4 mm, 50.4% (95% CI, 30.1–70.7%) of those with NT between 3.5 and 4.4 mm and 70.2% (95% CI, 32.0–94.9%) of those with NT ≄ 4.5 mm. Conclusion Increased NT measured in the early first trimester of pregnancy is associated with an increased risk of adverse pregnancy outcome, chromosomal, genetic and structural anomalies, and perinatal loss, even in case of its resolution at the time of the 11–14‐week scan. Ā© 2025 International Society of Ultrasound in Obstetrics and Gynecology.
Background Preimplantation genetic testing (PGT) has emerged as a pivotal technique in assisted reproductive technology for enhancing success rates by identifying euploid embryos prior to transfer. The optimal timing for … Background Preimplantation genetic testing (PGT) has emerged as a pivotal technique in assisted reproductive technology for enhancing success rates by identifying euploid embryos prior to transfer. The optimal timing for blastocyst biopsy during PGT remains controversial, with conflicting evidence regarding the clinical outcomes of day 5 (D5) versus day 6 (D6) biopsies, as well as neonatal and perinatal outcomes. Methods This study involved a retrospective analysis of 3,647 biopsied blastocysts and 673 PGT-frozen embryo transfer (FET) cycles conducted at Zhongshan Boai Hospital between May 2019 and September 2024. Patients were categorized into D5 and D6 biopsy groups. The study comprised three components: (1) a comparison of chromosomal euploidy, mosaicism, and aneuploidy rates between the two groups, along with an assessment of clinical, neonatal, and perinatal outcomes in PGT-FET cycles; (2) stratification based on embryo quality to compare clinical, neonatal, and perinatal outcomes in PGT-FET cycles between the two groups; and (3) stratification according to maternal age to compare clinical, neonatal, and perinatal outcomes in PGT-FET cycles between the two groups. Results The euploidy rate was significantly higher in D5 blastocysts compared to D6 blastocysts (47.53% vs. 32.38%, p &amp;lt; 0.01). In the PGT-FET cycles, the live birth rate in the D5 biopsy group was significantly higher than that in the D6 biopsy group (56.11% vs. 48.38%, p = 0.046); however, there were no significant differences in the clinical pregnancy rate, miscarriage rate, or neonatal outcome. Stratification by embryo quality revealed no significant differences in clinical pregnancy, live birth, or miscarriage rates for blastocysts of the same quality grade between the D5 and D6 biopsy groups. In the D5 biopsy group, variations in embryo quality did not affect clinical outcomes, whereas in the D6 biopsy group, high-quality blastocysts were associated with improved pregnancy and live birth rates. Age-stratified analysis showed similar clinical outcomes for PGT-FET in the D5 and D6 biopsy groups across different age groups. Conclusion Compared to D6, D5 biopsied blastocysts demonstrated higher euploidy and live birth rates. Therefore, it is recommended to prioritize biopsy at D5 and to thaw blastocysts at D5 for transfer to achieve better clinical pregnancy and neonatal outcomes.
Ribosomal DNA transcription is essential for ribosome biogenesis and the production of proteins. Using a combination of droplet digital PCR and deep bisulfite sequencing, we have quantified both the absolute … Ribosomal DNA transcription is essential for ribosome biogenesis and the production of proteins. Using a combination of droplet digital PCR and deep bisulfite sequencing, we have quantified both the absolute number as well as the methylation level of individual rDNA transcription units (TU) in blood samples of 139 young healthy individuals and 141 sex- and age-matched individuals with unsolved syndromal developmental delay (DD), ranging from 0.02 to 18.4 years in age. There were no between-group differences in average promoter methylation, absolute copy number (CN), extreme CN, and hypomethylated (0-10%) presumably active CN. This largely excludes rDNA CN as a modulating factor in DD. The absolute CN in all 280 samples was 423.7 ± 108.4 (median 410, range 153 to 1,000) and the active CN was 175.0 ± 36.4 (median 174, range 70 to 376). Similar to adults, the absolute CN did not change from birth to sexual maturity but was strongly (Pearson ρ = 0.64, P < 0.001) correlated with promoter methylation. In contrast to adults, there was no significant correlation between age and promoter methylation and no age-related loss of active copies from birth to < 20 years. The number of completely unmethylated copies even significantly (Pearson ρ = 0.15; P = 0.01) increased during childhood and adolescence. Our results suggest that rDNA promoter methylation and the age-related loss of active rDNA TU, which are a hallmark of the aging process, start only after reaching sexual maturity.
Unexpected pregnancy loss can be a traumatic experience for fertile couples. The aim of the study was to assess the nature and type of chromosomal variants involved in early and … Unexpected pregnancy loss can be a traumatic experience for fertile couples. The aim of the study was to assess the nature and type of chromosomal variants involved in early and late pregnancy loss and provide couples an explanation on the cause of their pregnancy loss. Investigations were conducted on 2928 pregnancy loss cases where products of conception (POC) samples could be retrieved for genetic analysis. Chromosomal variants were detected by low pass copy number variation sequencing (CNV-seq). In first-trimester miscarriages, 1272 of POC (60.4%) samples had a chromosome abnormality. Autosomal aneuploidy and monosomy X were the predominate variants (73.2%), followed by autosomal and sex chromosome mosaicism (10.7%), triploidy (9.6%), pathogenic CNVs (6.2%) and haploidy (0.3%). The chromosomal variants were similar in type and frequency regardless of whether the fetus had normal or abnormal ultrasound findings. In second trimester pregnancy loss where there was either a structural or non-structural ultrasound anomaly, only 15.3% of POC samples had a chromosome abnormality, involving mainly the smaller autosomes and monosomy X (55.7%), autosomal and sex chromosomal mosaicism (11.5%), triploidy (4.1%) and pathogenic CNVs (28.7%). Chromosomal variants contribute to fetal demise in almost two thirds of pregnancy losses.
ABSTRACT Background It is found to have association of facial parameters with trisomy 21 fetuses (T 21). We have compared prenasal thickness (PNT), nasal bone length (NBL), and the PNT:NBL … ABSTRACT Background It is found to have association of facial parameters with trisomy 21 fetuses (T 21). We have compared prenasal thickness (PNT), nasal bone length (NBL), and the PNT:NBL ratio of normal fetuses with fetuses with trisomy 21 (T 21) between 16 and 25 weeks of gestation as a diagnostic tool for T 21. Methods Facial profile images in the two dimensional (2D) gray scale were assessed to measure fetal NBL and PNT between 16 and 25 weeks of gestation. The PNT:NBL ratio of the fetuses was calculated. Nomograms were constructed from the data of morphologically normal fetuses at live birth. The PNT, NBL, and PNT:NBL ratio of fetuses with confirmed T 21 ( n = 31) and morphologically normal fetuses at live birth (controls, n = 3485) were compared. Results Nomograms for PNT, NBL, and the PNT:NBL ratio were constructed. In T 21 fetuses, PNT (&gt; 95th percentile), NBL (&lt; 5th percentile), and the PNT:NBL ratio (&gt; 95th percentile) showed a sensitivity of 25%, 29%, and 45% for PNT, NBL, and PNT:NBL, respectively, and specificity of 95%, 96%, and 94%, for PNT, NBL, and PNT:NBL, respectively. All of these markers showed a negative predictive value of 99%. Conclusion PNT, NBL, and the PNT:NBL ratio have high diagnostic value for fetuses with Down syndrome and can be incorporated easily in the current second trimester screening protocol for T 21. PNT, NBL, and the PNT:NBL ratio are more specific markers for Down syndrome than those used in previous studies.
Introduction and Objective: We tested a new fetal insulin secretion polygenic score (PRS) as a modifier of the relationship between maternal glucose and neonatal outcomes in the HAPO study. Methods: … Introduction and Objective: We tested a new fetal insulin secretion polygenic score (PRS) as a modifier of the relationship between maternal glucose and neonatal outcomes in the HAPO study. Methods: We built a fetal PRS with 7 independent variants associated with lower type 2 diabetes risk, higher birthweight, and higher corrected insulin response in prior GWAS, weighted using birthweight effects. We used logistic regression (adjusted for maternal age, BMI, study site, fetal genetic principal components) to test for interaction between the PRS and maternal glucose (fasting, 1- and 2-hr from oral glucose tolerance tests at 24-30 weeks’ gestation) with large for gestational age birthweight (&amp;gt;90th percentile, LGA), neonatal hypoglycemia (NH), and high cord blood C-peptide (&amp;gt;90th percentile), at Bonferroni-adjusted α=0.006. If there was evidence of PRS-glucose interaction, we built stratified models (top and bottom PRS quartiles) relating maternal glucose and outcomes. Results: Among N=5280 newborns, the PRS was associated with higher cord blood C-peptide (β=0.04; P=8.1x10-8) and birthweight percentile (β=1.31; P=3.8x10-4). There was a PRS-maternal 2-hr glucose interaction for LGA (P=2.7x10-4), with a weaker association between maternal 2-hr glucose and LGA in the top PRS quartile (OR=1.09, 95% CI 0.90-1.33) than in the bottom quartile (OR=1.53; 95% CI 1.22-1.92). There was a PRS-maternal 2-hr glucose interaction for NH (P=4.0x10-3), with a stronger association between maternal 2-hr glucose and NH in the top PRS quartile (OR=1.31; 95% CI 0.67-2.59) than in the bottom quartile (OR=0.54; 95% CI 0.23-1.24). There was a nominal PRS-fasting maternal glucose interaction for high cord blood C-peptide (P=0.01), with a stronger association between maternal fasting glucose and high C-peptide in the top PRS quartile (OR 2.54; 95% CI 1.98-3.25) than in the bottom quartile (OR 1.55; 95% CI 1.16-2.07). Conclusion: Fetal insulin secretion genetics modify associations of maternal glucose with LGA and NH. Disclosure S. Hsu: None. A. Kuang: None. J.L. Josefson: None. D. Scholtens: None. W.L. Lowe: None. C.E. Powe: Research Support; Dexcom, Inc. Other Relationship; Mediflix, Wolters Kluwer Health.
Chromosomal defects are a significant cause of perinatal death and childhood disability, occurring in 3.6–6.0 per 1000 births in unscreened populations. Common chromosomal defects include trisomy 21, 18, and 13, … Chromosomal defects are a significant cause of perinatal death and childhood disability, occurring in 3.6–6.0 per 1000 births in unscreened populations. Common chromosomal defects include trisomy 21, 18, and 13, triploidy, and sex chromosome abnormalities. Screening for these defects began in the mid-1960s with the advent of amniocentesis, and various methods have since been developed to improve screening performance. Initial screening was based solely on maternal and gestational age, a method incorporated later into all subsequent screening methods giving an a priori background risk. This a priori background risk, which is further refined by maternal serum biochemistry, results of ultrasound examinations, and most recently, results of non-invasive prenatal testing by cell-free DNA in maternal blood. This paper will describe methods of screening for all chromosomal defects and their performance. Unlike most reviews, this paper covers not only screening tests for Down syndrome, but also screening methods for the other most common and less common chromosomal defects.
Introduction: Chromosomal polymorphisms are variations in chromosomes in normal populations, generally affecting heterochromatic regions, which are poor in protein-coding genes. Several international studies associate the influence of chromosomal polymorphisms with … Introduction: Chromosomal polymorphisms are variations in chromosomes in normal populations, generally affecting heterochromatic regions, which are poor in protein-coding genes. Several international studies associate the influence of chromosomal polymorphisms with pregnancy loss.Objective: To analyze and characterize the frequency and types of chromosomal polymorphisms found in these patients, as well as to explore possible correlations between these variations and the different reproductive disorders observed.Methods: Patients with reproductive disorders who had a polymorphic variant of chromosomes 1, 9, 16, or Y and acrocentric chromosomes 13, 14, 15, 21, or 22 were selected. They were analyzed in different groups: recurrent pregnancy loss (I) and infertility (II). Results: Of 549 patients with reproductive disorders, chromosomal polymorphisms were detected in 61 (11%). The most frequent polymorphisms were 1qh-, 9qh+, 21pstk+, inv 9, and 16qh+. The group with recurrent miscarriages presented 45.4% of the most frequently found polymorphisms. Cases of infertility alone accounted for only 24.2%. In both groups analyzed, female patients predominated over males.Conclusions: The percentage of chromosomal polymorphisms found in the study sample is consistent with international reports on this topic. An unusual chromosomal polymorphism of chromosome 1 was found with relative frequency, which could constitute an inherent characteristic of the population studied. Chromosomal polymorphisms of chromosome 9 are the most recurrent finding involved in reproductive disorders.
Key content Cell‐free fetal DNA (cffDNA) screening test performance for sex chromosome aneuploidies (SCAs), copy number variants (CNVs), rare autosomal trisomies (RATs) and single gene disorders. cffDNA screening for detection … Key content Cell‐free fetal DNA (cffDNA) screening test performance for sex chromosome aneuploidies (SCAs), copy number variants (CNVs), rare autosomal trisomies (RATs) and single gene disorders. cffDNA screening for detection of pre‐eclampsia and malignancy. Investigation of recurrent miscarriage using cffDNA. Alternative approaches to interrogating free fetal DNA. Learning objectives To appreciate there is a lack of robust evidence regarding cffDNA screening test performance for expanded applications. To understand that some but not all countries endorse SCA screening and screening for some CNVs such as 22q.11.2 microdeletion syndrome. To be aware that expanded applications of cffDNA screening pose interpretational and ethical challenges. To be aware that the diagnostic confirmatory test of choice following a high‐chance screening result for the aforementioned conditions is an amniocentesis. Ethical issues Indirect sex determination may occur with SCA screening. Expanded applications for cffDNA screening in the UK fall outside recommendations.