Cell-free Fetal DNA Screening Research Articles

523 Fetal and Neonatal Outcomes after “Atypical Finding for Sex Chromosomes” on Cell-Free Fetal DNA Screening

523 Fetal and Neonatal Outcomes after “Atypical Finding for Sex Chromosomes” on Cell-Free Fetal DNA Screening

High sensitivity and specificity in fetal gender identification in the first trimester, using ultrasound and Noninvasive Prenatal Screening (NIPS) in twin pregnancies, a prospective study

IntroductionDetermination of the fetal gender in the first trimester is important in twin pregnancy cases of familial X-linked genetic syndromes and helps determine chorionicity. We assessed and compared the accuracy of first-trimester ultrasound scans, and cell-free fetal DNA (CfDNA) in determining fetal gender in the first trimester of twin pregnancies.MethodsWomen with twin pregnancies were recruited prospectively during the first trimester. Fetal gender was determined using both ultrasound scans and CfDNA screening. Both results were compared to the newborn gender after delivery.ResultsA total of 113 women with twin pregnancies were enrolled. There was 100% sensitivity and specificity in Y chromosome detection using CfDNA.Gender assignment using ultrasound in any first-trimester scans was 79.7%. Accuracy level increased from 54.2% in CRL 45-54 mm to 87.7% in CRL 55-67 mm and 91.5% in CRL 67-87 mm. Male fetuses had significantly higher chances of a gender assignment error compared to female fetuses, odds ratio = 23.574 (CI 7.346 - 75.656).ConclusionsCfDNA is highly sensitive and specific in determining the presence of the Y chromosome in twin pregnancies in the first trimester. Between CRL 55-87 mm, ultrasound scanning offers a highly accurate determination of fetal gender in twin pregnancies.

Cell-Free Fetal DNA Screening Analysis in Korean Pregnant Women: Six Years of Experience and a Retrospective Study of 9327 Patients Analyzed from 2017 to 2022.

Cell-free DNA (cfDNA) screening for normal fetal aneuploidy has been widely adopted worldwide due to its convenience, non-invasiveness, and high positive predictive rate. We retrospectively evaluated 9327 Korean women with single pregnancies who underwent a non-invasive prenatal test (NIPT) to investigate how various factors such as maternal weight, age, and the method of conception affect the fetal fraction (FF). The average FF was 9.15 ± 3.31%, which decreased significantly as the maternal body mass index (BMI) increased (p < 0.001). The highly obese group showed a 'no-call' rate of 8.01%, which is higher than that of the normal weight group (0.33%). The FF was 8.74 ± 3.20% when mothers were in their 40s, and lower than that when in their 30s (9.23 ± 3.34, p < 0.001) and in the natural pregnancy group (9.31% ± 3.33). The FF of male fetuses was observed to be approximately 2.76% higher on average than that of female fetuses. As the gestational age increased, there was no significant increase in the fraction of fetuses up to 21 weeks compared to that at 10-12 weeks, and a significant increase was observed in the case of 21 weeks or more. The FFs in the NIPT high-risk result group compared to that in the low-risk group were not significantly different (p = 0.62). In conclusion, BMI was the factor most associated with the fetal fraction. Although the NIPT is a highly prevalent method in prenatal analysis, factors affecting the fetal fraction should be thoroughly analyzed to obtain more accurate results.

Incidental Detection of Malignancies With Cell-Free DNA Screening.

Cell-free circulating DNA is an evolving technology with important clinical applications in both obstetric care and oncology. In the challenging patient with pregnancy and co-existing malignancy, the utility of cell-free DNA both for aneuploidy screening and cancer identification is an area of active research. Understanding the physiology associated with circulating cell-free DNA and subsequent laboratory evaluation is critical for clinicians caring for the obstetric patient with cell-free fetal DNA screening results suggestive of malignancy. Ongoing research is necessary to determine best practices for the evaluation and management of these patients with promising applications in the advancement of precision medicine.

Cytogenetic outcomes following a failed cell-free DNA screen: a population-based retrospective cohort study of 35,146 singleton pregnancies

Cell-free fetal DNA screening is routinely offered to pregnant individuals to screen for aneuploidies. Although cell-free DNA screening is consistently more accurate than multiple-marker screening, it sometimes fails to yield a result. These test failures and their clinical implications are poorly described in the literature. Some studies suggest that a failed cell-free DNA screening result is associated with increased likelihood of cytogenetic abnormalities. This study aimed to assess the association between a failed cell-free DNA test and common aneuploidies. The objectives were to determine: (1) the proportion of test failures on first and subsequent attempts, and (2) whether a failed cell-free DNA screen on first attempt is associated with increased likelihood of common aneuploidies (trisomies 21, 18, and 13, and sex chromosome aneuploidies). This was a population-based retrospective cohort study using data from Ontario's prescribed maternal and child registry, Better Outcomes Registry and Network Ontario. The study included all singleton pregnancies in Ontario with an estimated date of delivery from September 1, 2016 to March 31, 2019 that had a cell-free DNA screening record in the registry. Specific outcomes (trisomies 21, 18, and 13, and sex chromosome aneuploidies) of pregnancies with a failed cell-free DNA screen on first attempt were compared with those of pregnancies with low-risk cell-free DNA-screening results using modified Poisson regression adjusted for funding status (publicly funded vs self-paid), gestational age at screening, method of conception, and maternal age for autosomal aneuploidies. Our cohort included 35,146 pregnancies that had cell-free DNA screening during the study period. The overall cell-free DNA screening failure rate was 4.8% on first attempt and 2.2% after multiple attempts. An abnormal cytogenetic result for trisomies 21, 18, and 13, or sex chromosome aneuploidies was identified in 19.4% of pregnancies with a failed cell-free DNA screening for which cytogenetic testing was performed. Pregnancies with a failed cell-free DNA screen on first attempt had a relative risk of 130.3 (95% confidence interval, 64.7-262.6) for trisomy 21, trisomy 18, or trisomy 13, and a risk difference of 5.4% (95% confidence interval, 2.6-8.3), compared with pregnancies with a low-risk result. The risk of sex chromosome aneuploidies was not significantly greater in pregnancies with a failed result compared with pregnancies with a low-risk result (relative risk, 2.7; 95% confidence interval, 0.9-7.9; relative difference, 1.2%; 95% confidence interval,-0.9 to 3.2). Cell-free DNA screening test failures are relatively common. Although repeated testing improves the likelihood of an informative result, pregnancies with a failed cell-free DNA screen upon first attempt remain at increased risk for common autosomal aneuploidies, but not sex chromosome aneuploidies.

High fetal fraction on cell-free fetal DNA screening: is it associated with adverse perinatal outcomes?

High fetal fraction on cell-free fetal DNA screening: is it associated with adverse perinatal outcomes?

Fetal Disseminated Malignant Rhabdoid Tumor.

Fetal Disseminated Malignant Rhabdoid Tumor.

Positive predictive value estimates for noninvasive prenatal testing from data of a prenatal diagnosis laboratory and literature review

ObjectiveSince 2011, noninvasive prenatal testing (NIPT) has undergone rapid expansion, with both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this testing tool are lacking. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations in order to inform pre- and post-test counseling, pre/perinatal decision making, and medical risk assessment/management.MethodsThis retrospective study included women referred for invasive prenatal diagnosis to confirm positive NIPT results between January 2017 and December 2020. Prenatal diagnosis testing, including karyotyping, chromosomal microarray analysis (CMA) were performed. Positive predictive values (PPVs) were calculated.ResultsIn total, 468 women were recruited. The PPVs for trisomies 21, 18, and 13 were 86.1%, 57.8%, and 25.0%, respectively. The PPVs for rare chromosomal abnormalities (RCAs) and copy number variants (CNVs) were 17.0% and 40.4%, respectively. The detection of sex chromosomal aneuploidies (SCAs) had a PPV of 20% for monosomy X, 23.5% for 47,XXX, 68.8% for 47,XXY, and 62.5% for 47,XYY. The high-risk groups had a significant increase in the number of true positive cases compared to the low- and moderate-risk groups.ConclusionsT13, monosomy X, and RCA were associated with lower PPVs. The improvement of cell-free fetal DNA screening technology and continued monitoring of its performance are important.

Comparison of the Fetal Fraction of Cell-Free DNA in In-Vitro Fertilization (IVF) Versus Natural Conception Evaluation of the Fetal Fraction With IVF Parameters.

BackgroundAs the offspring of assisted reproduction techniques (ARTs) have become a substantial proportion of the population, increased attention has been placed on the safety of ART. Investigators have focused on identifying a tool that combines molecular or biological tests that can predict the outcomes of in-vitro fertilization (IVF) or intracytoplasmic sperm injection and the resulting pregnancy after ART-mediated embryo implantation. This study aimed to answer the following questions: is there a difference between natural conception and IVF pregnancies regarding fetal fraction (FF) of cell-free DNA (cfDNA) in maternal age, birth weight, gender, and gestational age? Is there a difference between FF concentration regarding the parameters of IVF as possible predictive factors affecting the outcomes of IVF?MethodologyThis study included 31 women with singleton pregnancies conceived via IVF who underwent cell-free fetal DNA (cffDNA) screening for trisomy 13, 18, and 21; sex determination; and FF. The control group included 55 women who experienced natural conception. For all women, anthropometric characteristics such as age, weight, height, and body mass index (BMI) were recorded. For the IVF group, early follicular phase values of follicle-stimulating hormone, luteinizing hormone, prolactin, anti-müllerian hormone, thyroid-stimulating hormone, and estradiol were recorded.ResultsThe natural conception and IVF groups were similar regarding maternal age, BMI of the mother, gender, birth weight, and gestational age. FF was not significantly different between the natural conception and IVF groups (10 (3.8) vs. 9 (2.6); p = 0.144). The results were similar after adjusting for maternal age via regression analysis. cfDNA was not associated with maternal age, birth weight, gender, or gestational age in the entire study sample or separately for the natural conception and IVF groups. No significant correlation was found between cfDNA and IVF parameters.ConclusionsThe FF is an important factor for non-invasive prenatal testing (NIPT) accuracy. Several studies have found a reduction in FF in pregnancies following ART compared with natural conception, while other studies have presented no differences in the FF. All researchers agree on the importance of NIPT; however, knowledge on how the FF is affected in ART pregnancies compared with naturally conceived pregnancies is very limited. In this study, no difference in FF for the IVF group compared with natural conception women was observed. The cffDNA concentrations in maternal serum do not appear to be affected in IVF conception. We suggest that FF is an independent factor compared with IVF parameters.

Correction to “Performance of a universal prenatal screening program incorporating cell-free fetal DNA analysis in Ontario, Canada”

CMAJ has been made aware of an error that occurred in the Aug. 3, 2021, issue.[1][1] In Figure 3, the number of pregnant people in Ontario who underwent first-tier cell-free fetal DNA screening should have been 5750, not 575. This has been corrected at [cmaj.ca][2]. 1. [↵][3]1. Dougan SD

Current attitudes and preconceptions towards expanded carrier screening in the Eastern Chinese reproductive-aged population.

A growing number of Chinese individuals of reproductive age will face the choice of accepting or refusing expanded carrier screening (ECS). This study aimed to explore the awareness, wishes, and possible misconceptions of ECS among this population, as well as factors affecting their decision-making. Chinese reproductive-aged individuals in Eastern China who sought cell-free fetal DNA screening and peripheral blood karyotype were invited to complete a 31-item ECS survey by scanning a specific quick response code. We evaluated the relationship between awareness, attitudes, and intentions to participate in ECS, along with possible misconceptions. Overall, 93.1% of participants intended to undergo ECS at their expenses, and 53.6% indicated they would pay less than 1000 CNY (approximately 145 USD) for the test. Around 96.5% of participants had misconceptions about ECS and genetic diseases. Participants whose first reaction was interest, who had prior awareness of the test, or who perceived benefits were more likely to intend to use ECS (p < 0.001). Participants with a bachelor's degree or above or with a household income over 150,000 CNY (approximately 21,700 USD) would be more likely to pay ≥ 1000 CNY (p < 0.05). Our study indicates that overall, the Eastern Chinese reproductive-aged population has positive attitudes towards ECS, although there are some misconceptions about ECS and genetic disorders. Population-based ECS appears to be desired by the reproductive-aged people in Eastern China. Steps should be taken to offer ECS along with pre- and post-test education and genetic counseling to raise awareness and to reduce misconceptions.

Relevance of Invasive Testing in Era of Non-Invasive Testing for Prenatal Chromosomal Abnormalities

Prenatal screening for chromosomal abnormalities has two components i.e. prenatal screening (maternal serum screening and cell-free fetal DNA screening) and prenatal diagnosis (chorionic villus sampling, amniocentesis, and cordocentesis). Prenatal testing in the past decade is evolving towards non-invasive methods to determine the chromosome abnormality disorders in the fetus without incurring the risk of miscarriage. Conventional tools for prenatal screening included maternal age, maternal serum markers, ultrasound marker (nuchal thickness), and their combinations. With the increased risk of screening test patients were offered diagnostic tests (chorionic villus sampling, amniocentesis, and cordocentesis). After the availability of noninvasive prenatal tests for commercial use in 2011, a great marketing drive is there to establish it as a master tool for prenatal testing. However various society guidelines i.e. ACOG, RCOG, and ISUOG have clearly stated that cell-free fetal DNA based noninvasive prenatal tests is a screening test, not a diagnostic test. In the succeeding paragraph, we will review current trends in the field of cell-free fetal DNA noninvasive prenatal tests and the relevance of invasive testing in the context of noninvasive prenatal tests. Noninvasive prenatal tests does not entirely replace invasive prenatal testing procedures. Positive noninvasive prenatal tests findings must be confirmed by diagnostic tests based on an invasive sample source, mainly chorionic villus sampling or amniocentesis due to false positive and false negative reports of cell-free fetal DNA based tests. Continuing research and development efforts are focused on overriding noninvasive prenatal tests limitations. Recent studies show that procedure-associated risks in the case of prenatal invasive testing are very low as compared to previous studies. Prenatal invasive testing will remain as the backbone of prenatal diagnostic testing until the limitation of noninvasive prenatal tests is overcome.

Prenatal screening for trisomy 21: a comparative performance and cost analysis of different screening strategies

BackgroundPrenatal screening for chromosome aneuploidies have constantly been evolving, especially with the introduction of cell-free fetal DNA (cfDNA) screening in the most recent years. This study compares the performance, costs and timing of test results of three cfDNA screening implementation strategies: contingent, reflex and primary.MethodsWe modelled enhanced first trimester screening (eFTS) as the first-tier test in contingent or reflex strategies. cfDNA test was performed contingent on or reflex from eFTS results. A comparison was made between cfDNA screening using sequencing technology and Rolling Circle Amplification (RCA)/imaging solution. All model assumptions were based on results from previous publications or information from the Ontario prenatal screening population.ResultsAt an eFTS risk cut-off of ≥1/1000, contingent and reflex cfDNA screening have the same detection rate (DR) (94%) for trisomy 21. Reflex cfDNA screening using RCA/Imaging solution provided the lowest false positive rate and cost. The number of women requiring genetic counselling and diagnostic testing was significantly reduced and women received their cfDNA screening result 9 days sooner compared with the contingent model. While primary cfDNA screening improved the trisomy 21 DR by 3–5%, it was more costly and more women required diagnostic testing.ConclusionReflex cfDNA screening is the most cost-effective prenatal screening strategy. It can improve the efficiency of prenatal aneuploidy screening by reducing the number of patient visits and providing more timely results.

Vein of Galen Malformation.

* Abbreviations: CPAP: : continuous positive airway pressure Fio2: : fraction of inspired oxygen MFCC: : Maternal Fetal Care Clinic MRA: : magnetic resonance angiography MRI: : magnetic resonance imaging MRV: : magnetic resonance venography PGE1: : prostaglandin E1 VOGM: : vein of Galen malformation A 37-year-old gravida 3, para 1 pregnant woman was referred to the Maternal Fetal Care Center (MFCC) at Boston Children’s Hospital at 36 weeks’ gestation for the finding of vein of Galen malformation (VOGM). The patient’s pregnancy was complicated by gestational diabetes. Her surgical history was notable for adenoidectomy, a previous cesarean section, and dilation and curettage following a spontaneous abortion. Maternal medications included prenatal vitamins and glyburide. Family history was noncontributory. This pregnancy was planned and naturally conceived. The woman received appropriate prenatal care. Noninvasive prenatal screening showed her to be at low risk and cell-free fetal DNA screening was negative. She had a normal anatomy scan at 20 weeks’ gestation. Fetal ultrasonography performed at 36 weeks' gestation for evaluation of fetal growth demonstrated a prominent rounded vascular structure in the quadrigeminal cistern with turbulent flow consistent with a VOGM. Fetal echocardiography at that time revealed dilation of the right atrium and right ventricle with normal biventricular function. There was no evidence of hydrops. Imaging at 37 weeks’ gestation in the Boston Children’s Hospital MFCC included repeat comprehensive fetal echocardiography, fetal ultrasonography, and fetal brain magnetic resonance imaging (MRI). Echocardiography revealed a markedly enlarged right atrium and right ventricle with mild right ventricular dysfunction. Moderate tricuspid regurgitation was noted, the innominate vein was markedly dilated, and the superior vena cava had increased flow. The interventricular septum was dyskinetic, suggesting increased pressure within the right ventricle. There was a patent foramen ovale and a patent ductus arteriosus with right-to-left shunting throughout the cardiac cycle. No evidence of pericardial effusion or hydrops fetalis was seen. Fetal ultrasonography showed a singleton male fetus with biometry measurements, including head circumference, corresponding to estimated gestational age. Amniotic fluid volume was normal. The fetal survey demonstrated a large midline intracranial vascular structure in the expected …

Twin anemia–polycythemia sequence in sex‐discordant monochorionic dizygotic twins

The possibility of monochorionic (MC) dizygotic (DZ) twins was first raised in 1970. As MC sex-discordant twins are rarely observed, MCDZ twins are seldom recognized clinically. Conception by assisted reproductive technology (ART) is associated with an increased frequency of MC diamniotic (DA) twins, with more than 50% of reported MCDZ twins conceived by ART1. With the increased use of ART, it is therefore reasonable to expect that the incidence of MCDZ twins may increase. MC twins share a single placenta and are connected by the placental circulation. They are at risk of transfusion imbalance in this circulation, which may lead to twin–twin transfusion syndrome (TTTS) or twin anemia–polycythemia sequence (TAPS). The diagnosis of TTTS at an early stage is based on discordant amniotic fluid volume. Currently, the diagnosis of TAPS is based on increased middle cerebral artery peak systolic velocity (MCA-PSV) in the donor twin (> 1.5 MoM) and decreased MCA-PSV in the recipient twin (< 1 MoM)2. Postnatally, TAPS can be diagnosed based on an intertwin hemoglobin difference of > 8 g/dL and at least one of the following criteria: (1) reticulocyte count ratio > 1.7; and (2) presence of only small vascular anastomoses on placental examination3. We report a case of TAPS diagnosed prenatally in a MCDZ twin pregnancy. A 32-year-old woman with a spontaneously conceived pregnancy was diagnosed with a MCDA twin gestation at 14 weeks by ultrasound. Sex discordance was noted on the fetal anatomy survey and was suggested on cell-free fetal DNA screening. Sex discordance was confirmed postnatally. A diagnosis of TAPS was suspected at 28 + 6 weeks based on MCA-PSV (1.65 MoM in the donor and 0.48 MoM in the recipient), and worsening of TAPS, with a new finding of placental echogenicity discordance between the donor and recipient sides, was suspected at 30 + 6 weeks (Figure 1). The patient was delivered at 31 + 2 weeks, following administration of corticosteroids and magnesium sulfate for neuroprotection, due to worsening of TAPS. TAPS was confirmed postnatally. Hemoglobin was 25.2 g/dL in the recipient twin and 7.5 g/dL in the donor twin. Reticulocyte count ratio (donor/recipient twin) was 14.7. Monochorionicity was confirmed by pathological examination. In TAPS, the placenta may have a discordant ultrasound appearance (hyperechoic on the donor twin side and hypoechoic on the recipient twin side) and a color difference on gross examination (pale appearance on the donor twin side and dark purple appearance on the recipient twin side)4. The current case demonstrated these findings (Figures 1 and 2). Although a case of TAPS in MCDZ twins was reported recently in a spontaneously delivered pregnancy in which the diagnosis was made postnatally5, we report what we believe to be the first case of TAPS in MCDZ twins that was diagnosed prenatally. Our report demonstrates that discordant MCA-PSV measurements and placental echogenicity differences in MC twin pregnancy are objective ultrasound findings that may indicate a developing and worsening status of TAPS in MCDZ twins. It is important to recognize that MCDZ twin gestations exist. Early determination of chorionicity during the first trimester with confirmation of fetal sex in the second trimester is the key in identifying a MCDZ twin gestation.

226: Cell-free DNA fetal fraction and pregnancy outcome

Fetal cell-free DNA from maternal plasma during pregnancy is a fairly new technology that is increasingly being used to screen for aneuploidy. Limited reports show that low and high fetal fraction percentages may be associated with increased risks of adverse pregnancy outcomes. The purpose of this study is to determine if high or low fetal fraction percentages are associated with adverse pregnancy outcomes to include hypertensive disorders, low birth weight, and preterm delivery. A retrospective chart review was performed evaluating pregnancy outcomes for 200 patients who underwent cell-free fetal DNA screening from January 2016 until October 2017. The estimated gestational age at delivery, birth weight, and presence or absence of hypertensive disorders was recorded and their association with their fetal fraction percent was evaluated. The mean fetal fraction percent was 11.9%. Average gestational age at collection was 17 1/7 weeks. A distinct bimodal distribution at the time of collection was noted (less versus greater than 20 weeks). Fetal fraction percent was directly related to gestational age at collection and inversely related to patient’s weight and body mass index. Patients with low fetal fraction percents had more than twice the rates of hypertensive disorders compared to patients with higher fetal fraction percents (34.6% versus 14.2%, P< .05). Low fetal fractions drawn prior to 20 weeks gestational age had more than 3 times the rate of preterm delivery (31% versus 9%, p< .05). For patients undergoing screening after 20 weeks gestational age, a high fetal fraction percent was associated with lower birth weight (mean birth weight 3056g versus 3457g, p< .05) High and low fetal fraction percentages are markers for adverse pregnancy outcomes such as hypertensive disorders, low birth weight, and preterm delivery. Patients with such values may warrant closer monitoring during their pregnancy with additional appointments, blood pressure assessments, ultrasound assessments, and further education regarding the signs and symptoms of preeclampsia and preterm labor.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Usefulness and reliability of cell free fetal DNA screening for main trisomies in case of atypical profile on first trimester maternal serum screening

BackgroundPatients with atypical values of HCG and/or PAPP-A are at higher risk of chromosomal abnormality and vascular complications of pregnancy. The performance of cfDNA in this particular population has not yet been evaluated.ObjectivesThe primary objective was to evaluate the usefulness and reliability of cfDNA in screening for trisomy 21, 18 and 13 for patients with HCG < 0.25 multiple of median (MoM), HCG > 5.0 MoM and/or PAPP-A < 0.25 MoM, PAPP-A > 2.5 MoM. The secondary objective was to evaluate the contribution of cfDNA assay for the prediction of pregnancy’s vascular complications.MethodBetween June 2016 and July 2017, we analysed a women cohort from all over France who had at least one first trimester serum biomarker outside of normal range, in a retrospective, observational and multicentre study. Patients were included if they had a single pregnancy, normal first trimester ultrasound examination, whatever the result of the combined first trimester screening test was. The cfDNA was analysed by massive parallel sequencing technique. The accuracy of cfDNA assay was evaluated by calculation of sensitivity and specificity, and multivariate regression analysis was used to search for predictive factors for pregnancy’s vascular complications.ResultsAmong the 498 patients who underwent a cfDNA assay in this context, twenty-one (4.2%) were excluded because of loss to follow-up. Out of 477, test failure occurred for four patients initially, reduced to two patients (0.4%) after redrawn. CfDNA was positive for Trisomy 21 (n = 19), Trisomy 18 (n = 6) and Trisomy 13 (n = 1) and negative in 449. The sensitivity of cfDNA assay for trisomy 21 screening was 100% (19/19) (IC 95% 82.4–100) and specificity 100% (458/458) (IC 95% 99.2–100). Among the 447 patients included for prediction of vascular complications, there were four cases of pregnancy induced hypertension and 10 cases of preeclampsia, for which no predictive factor was identified. Intra Uterine growth restriction under 5th percentile (n = 44, 9.8%) was significantly associated with a low fetal fraction (OR = 0.87, IC 95% 0.79–0.96, p = 0.006).ConclusioncfDNA assay is an effective and reliable tool for women with atypical profile of first trimester serum biomarkers.

Cell-free fetal DNA screening for detection of microdeletion syndromes: a cost-effectiveness analysis

Objective Fetuses with genetic copy number variants are poorly detected through traditional prenatal screening. Microdeletions and duplications are clearly identified with diagnostic testing through chromosomal microarray, and screening of a select number of microdeletions has become available with cell-free DNA (cfDNA). Our study compares the costs and outcomes of cfDNA for five pathogenic microdeletions and aneuploidy to cfDNA for aneuploidy alone in conjunction with ultrasound. Methods A decision-analytic model was constructed using TreeAge software to compare cfDNA with microdeletions versus traditional cfDNA in a theoretical cohort of 4,000,000 pregnancies that would also be screened with ultrasound. Probabilities, costs, and utilities were derived from literature. The primary outcomes were the incremental cost per quality-adjusted life-year (QALY), terminations, and procedure-related losses. Because the microdeletion results are available, but not reported, on all cfDNA testing we set the incremental cost of the cfDNA microdeletion screening test to zero at baseline and varied the cost in sensitivity analysis. Results Screening with cfDNA for microdeletions among all pregnant women would result in 83 fewer anomalous neonates compared to traditional cfDNA with ultrasound. This reduction is due to increased diagnosis and termination of fetuses with microdeletions in this group. Routine use of cfDNA with microdeletions resulted in more procedure-related losses. cfDNA with microdeletions would improve effectiveness by 977 QALYs and decrease costs by $90,991,784. When we varied the specificity of the screening test, we found that it remained cost-effective down to a specificity of 91%. With a threshold of $100,000/QALY, microdeletion screening is cost-effective to an incremental increase in cost over cfDNA for aneuploidy alone of $47.10. Conclusion For detection of fetal subchromosomal abnormalities, use of cfDNA with microdeletions is a cost-effective strategy compared to cfDNA for aneuploidy alone in conjunction with ultrasound. Cell-free DNA for microdeletions is not currently recommended as routine screening for low-risk obstetric populations by the American College of Obstetrics and Gynecologists or the Society for Maternal–Fetal Medicine. The test characteristics of cfDNA with microdeletions require greater examination before being routinely recommended.

Obstetric management, tests, and technologies that impact childhood development.

Childhood brain development begins before birth, and obstetric management, tests, and technologies designed to diagnose and treat fetal conditions can have an impact on development. Preconception counseling for maternal diabetes and hypertension affect the risk of fetal congenital anomalies and growth restriction. Patients with risk factors for pre-existing maternal diabetes are offered early diabetic screening because earlier diagnosis and treatment can decrease the risk of fetal and neonatal complications. Screening for chromosomal abnormalities in the first or second trimester is offered to all females regardless of age. Cell-free fetal DNA screening can be used to test for fetal genetic abnormalities as early as 9weeks of gestation with results available in 10days. Ultrasound performed around 20weeks' gestation can identify the 3% of fetuses that have a major congenital malformation. Fetal magnetic resonance imaging can be used to better assess fetal central nervous system abnormalities when neurosonography is inconclusive. Doppler ultrasound can be used to assess blood flow in the umbilical artery and fetal middle cerebral artery to aid in the management of the growth-restricted fetus. In summary, diagnosis and treatment of maternal and fetal conditions from the preconception period throughout pregnancy are important for optimizing fetal health and provide the best opportunity for optimal child development. WHAT THIS PAPER ADDS: Cell-free fetal DNA screening can identify fetal genetic abnormalities as early as 9weeks' gestation. Ultrasound performed around 20weeks' gestation can detect major fetal congenital malformations. Fetal magnetic resonance imaging can aid neurosonography in the assessment of fetal central nervous system abnormalities. Doppler ultrasound to assess fetal blood flow is used to successfully manage the growth-restricted fetus.

885: Cell-free fetal DNA screening for detection of microdeletion syndromes: A cost-effectiveness analysis

Copy number variants including microdeletion syndromes are poorly detected through traditional screening. While they can be diagnosed with invasive testing with chromosomal microarray analysis, cell-free DNA (cf DNA) screening is also currently available for detection of select microdeletions. Our study aims to investigate the costs and outcomes associated with detection of five microdeletion syndromes, using cf DNA to screen for microdeletions and aneuploidy compared to cf DNA for aneuploidy alone but in conjunction with ultrasound. A decision-analytic model was constructed using TreeAge software to compare cf DNA with microdeletions versus cf DNA with aneuploidies plus ultrasound in a theoretical cohort of 4,000,000 pregnancies for detection of 22q11.2, Prader-Willi, Angelman, Cri-du-chat, and 1p36 deletion syndromes. All probabilities, costs, and utilities were derived from literature. The primary outcome was incremental cost per quality-adjusted life year (QALY) in addition to terminations and procedure-related losses. Because the microdeletion results are available on all cf DNA testing, we set the incremental cost of cf DNA microdeletion screening to zero at baseline, but varied the cost in sensitivity analysis. Screening with cf DNA for microdeletions among all pregnant women would result in 75 fewer anomalous neonates as compared to cf DNA with ultrasound (Table). This reduction is due to increased termination rates of fetuses with microdeletions in this group. Routine use of cf DNA with microdeletions resulted in more procedure- related losses and losses of normal fetuses. cf DNA with microdeletions would improve effectiveness by 752 QALYs and decrease cost by $83,524,493. When we varied the specificity of the screening test, we found that it remained cost-effective down to a specificity of 92%. With a threshold of $100,000/QALY, microdeletion screening is cost- effective up until an incremental cost over cf DNA for aneuploidy alone of $39.60 (Figure). For fetal detection of subchromosomal abnormalities in pregnancy, cf DNA with microdeletions is a cost-effective strategy compared to cf DNA for aneuploidies and ultrasound. The test characteristics of cf DNA with microdeletions require greater examination and study before being routinely recommended.View Large Image Figure ViewerDownload Hi-res image Download (PPT)