Aneuploidy Screening Research Articles

The Natural History of Fetal Triploidy in an Era of Limited Abortion Access: A Case Series [ID: 1380133

INTRODUCTION: Triploidy is a chromosomal abnormality that occurs in 1–3% of all conceptions and often results in early spontaneous miscarriage. It is exceedingly rare for a triploid fetus to survive to birth. Neonates usually die within hours to days after delivery. After the Dobbs v Jackson Women's Health Organization ruling in July 2022, access to abortion is becoming increasingly limited, and therefore providers should consider the adverse maternal health outcomes that can be associated with triploidy. METHODS: In this case series, we describe three cases of confirmed fetal triploidy that we encountered in our center within 1 year (2021–2022). All three cases were referred to us after House Bill 1259 was passed on July 1, 2020, in Mississippi banning termination of pregnancy based on race, sex, or genetic abnormality. RESULTS: Our first case is a 21-year-old patient referred at 19 weeks 2 days for abnormal second-trimester serum screen. Ultrasound showed an enlarged multicystic placenta and multiple fetal anomalies. Amniocentesis showed a 69,XXY karyotype. Patient was managed expectantly. At 21 week 5 days, patient was diagnosed with superimposed preeclampsia with severe features. Patient underwent medical termination of pregnancy. The second case is a 25-year-old referred at 30 weeks 0 days for concerns of fetal anomalies. Ultrasound confirmed multiple fetal anomalies. Amniocentesis showed a 69,XXY karyotype. Patient was diagnosed with preeclampsia and pulmonary edema and was delivered at 30 weeks 1 day. The neonate passed away at 22 days of life. Our third case is a 20-year-old referred at 24 weeks 0 days for abnormal aneuploidy screening. Ultrasound showed a major cardiac defect and severe fetal growth restriction. Amniocentesis showed a 69,XXY karyotype. Patient was managed expectantly. At 29 weeks 0 days, intrauterine fetal demise was diagnosed. Patient was diagnosed with peripartum depression. CONCLUSION: Women with pregnancies affected by fetal triploidy are at risk of developing preeclampsia. Restricting access to abortion will lead to increased maternal morbidity and mortality rates.

Effect of accessibility of a genetic counselor on uptake of preimplantation genetic testing for aneuploidy (PGT-A) and carrier screening for patients undergoing in vitro fertilization.

This retrospective cohort study assessed the accessibility of a genetic counselor on uptake of preimplantation genetic testing for aneuploidy (PGT-A) and carrier screening in a single academic Reproductive Endocrinology and Infertility (REI) clinic. A total of 420 patients were evaluated with 219 patients counseled by a REI physician only and 201 patients after the addition of a genetic counselor (GC) to the REI clinic team. Cycles initiated before hiring of a GC (pre-GC) were assessed from June 2018 to December 2018 and after integration of a GC (post-GC) from March 2019 to August 2019. Additionally, information regarding carrier screening was collected if available in the medical record. Results showed more patients utilized PGT-A post-GC (9.5% vs. 5.5%), although the difference between groups did not reach statistical significance (p=0.12). Individuals who were screened post-GC or who started screening pre-GC and continued screening post-GC were screened for a larger number of conditions than if they were only screened pre-GC (median pre-GC=3, post-GC=27, pre- and post-GC=274; p < 0.0001). The change in practice from using physician-only counseling to counseling with accessibility to a GC did not change the utilization of PGT-A in a single clinic.

Evaluation of The Effects of Different Progesterone Treatment Methods on Fetal Aneuploidy Screening Tests

In this study, the effect of progesterone use on biomarkers due to abortion complaints in aneuploidy screenings was investigated. Two hundred seventy-six singleton pregnant patients with threatened abortion were enrolled in this retrospective study. The treatment group consisted of patients who received oral, vaginal, or intramuscular progesterone (n=137) while the control group received no progesterone (n=139). The results of the double and triple screening tests of the study groups were compared. Nuchal translucency measurements and pregnancy-associated plasma protein-A (PAPP-A), (MoM) values were significantly lower in the group that received treatment with progesterone compared to the control group (p=0.009 and p&amp;lt;0.001, respectively). Beta-human chorionic gonadotropin (βhCG), (MoM) and alpha-fetoprotein (MoM) were found to be statistically significantly higher in the group receiving oral progesterone treatment compared to the group receiving other types of progesterone treatment (p=0.032 and p=0.001, respectively). The PAPP-A was found to be significantly lower in the oral treatment group (p=0.001). It was also significantly lower in the hydroxyprogesterone caproate treatment group (p=0.013). In the vaginal progesterone treatment group, βhCG was significantly lower (p=0.036) than that in oral treatment group. The study showed that there is a relationship between different progesterone administration routes and fetal aneuploidy screening markers.

Clinical application of noninvasive prenatal testing in twin pregnancies: a single-centre experience

Objectives To evaluate the clinical efficiency of non-invasive prenatal testing (NIPT) for fetal chromosomal aneuploidy screening in twin pregnancies. Methods A total of 1650 women with twin pregnancies were enrolled in the study, which underwent NIPT at the Southwest Hospital, Army Medical University, Chongqing, China from January 2013 to June 2022. Fetal karyotyping analysis was conducted in high-risk patients, with subsequent follow-up on pregnancy outcomes. Results In 1650 pregnancies, NIPT results showed ten cases of the fetal chromosome aneuploidy, of which six cases were true positive and four cases were false positive. The sensitivity, specificity, positive predictive value (PPV), and false-positive rate (FPR) of trisomy 21 were 100%, 99.79%, 57.14%, and 0.18%, respectively. Sensitivity, specificity, PPV, and FPR of trisomy 18 were 100%, 99.94%, 50%, and 0.06%, respectively. The sensitivity, specificity, PPV, and FPR of trisomy 13 were 100%, 100%, 100%, and 0%, respectively. No false negatives were detected and the negative predictive value (NPV) was 100% of the total. Eleven pregnancies failed the NIPT test with no-call due to the low fetal fraction (< 4%). Conclusions NIPT is a high-performing routine primary prenatal screening test in twin pregnancies, with high sensitivity and specificity in screening for fetal aneuploidy.

Obstetrical, perinatal, and genetic outcomes associated with nonreportable prenatal cell-free DNA screening results

The clinical implications of nonreportable cell-free DNA screening results are uncertain, but such results may indicate poor placental implantation in some cases and be associated with adverse obstetrical and perinatal outcomes. This study aimed to assess the outcomes of pregnancies with nonreportable cell-free DNA screening in a cohort of patients with complete genetic and obstetrical outcomes. This was a prespecified secondary analysis of a multicenter prospective observational study of prenatal cell-free DNA screening for fetal aneuploidy and 22q11.2 deletion syndrome. Participants who underwent cell-free DNA screening from April 2015 through January 2019 were offered participation. Obstetrical outcomes and neonatal genetic testing results were collected from 21 primary-care and referral centers in the United States, Europe, and Australia. The primary outcome was risk for adverse obstetrical and perinatal outcomes (aneuploidy, preterm birth at <28, <34, and <37 weeks' gestation, preeclampsia, small for gestational age or birthweight <10th percentile for gestational week, and a composite outcome that included preterm birth at <37 weeks, preeclampsia, small for gestational age, and stillbirth at >20 weeks) after nonreportable cell-free DNA screening because of low fetal fraction or other causes. Multivariable analyses were performed, adjusting for variables known to be associated with obstetrical and perinatal outcomes, nonreportable results, or fetal fraction. In total, 25,199 pregnant individuals were screened, and 20,194 were enrolled. Genetic confirmation was missing in 1165 (5.8%), 1085 (5.4%) were lost to follow-up, and 93 (0.5%) withdrew; the final study cohort included 17,851 (88.4%) participants who had cell-free DNA, fetal or newborn genetic confirmatory testing, and obstetrical and perinatal outcomes collected. Results were nonreportable in 602 (3.4%) participants. A sample was redrawn and testing attempted again in 427; in 112 (26.2%) participants, results were again nonreportable. Nonreportable results were associated with higher body mass index, chronic hypertension, later gestational age, lower fetal fraction, and Black race. Trisomy 13, 18, or 21 was confirmed in 1.6% with nonreportable tests vs 0.7% with reported results (P=.013). Rates of preterm birth at <28, 34, and 37 weeks, preeclampsia, and the composite outcome were higher among participants with nonreportable results, and further increased among those with a second nonreportable test, whereas the rate of small for gestational age infants was not increased. After adjustment for confounders, the adjusted odds ratios were 2.2 (95% confidence interval, 1.1-4.4) and 2.6 (95% confidence interval, 0.6-10.8) for aneuploidy, and 1.5 (95% confidence interval, 1.2-1.8) and 2.1 (95% confidence interval, 1.4-3.2) for the composite outcome after a first and second nonreportable test, respectively. Of the patients with nonreportable tests, 94.9% had a live birth, as opposed to 98.8% of those with reported test results (adjusted odds ratio for livebirth, 0.20 [95% confidence interval, 0.13-0.30]). Patients with nonreportable cell-free DNA results are at increased risk for a number of adverse outcomes, including aneuploidy, preeclampsia, and preterm birth. They should be offered diagnostic genetic testing, and clinicians should be aware of the increased risk of pregnancy complications.

Does PGT-A affect cumulative live birth rate?

Preimplantation genetic testing for the purpose of aneuploidy screening (PGT-A) has increased in use over the last decade. Whether PGT-A benefits all of the patients that choose to employ it has been a concern, as recent studies have highlighted a potential decrease in cumulative live birth rate (CLBR) for younger patients undergoing embryo transfer. However, there are limitations to many of these studies and the intended benefit of PGT-A, which is to aid as a selection tool, thus increasing the live birth rate per transfer, must not be ignored. PGT-A was never intended to increase CLBR. The purpose of PGT-A is to maximize the chance at live birth per transfer while minimizing the risk of clinical miscarriage, ongoing aneuploid pregnancy and futile transfers. However, if it harms CLBR in the process that has to be taken into consideration. This review will discuss PGT-A in terms of its benefits, risks, and how it has been shown to affect the cumulative live birth rate within in-vitro fertilization cycles.

Prenatal screening for preeclampsia: the roles of placental growth factor and pregnancy–associated plasma protein A in the first trimester and placental growth factor and soluble fms-like tyrosine kinase 1–placental growth factor ratio in the early second trimester

Professional societies have recommended universal first trimester screening for preeclampsia and a second or third trimester soluble fms-like tyrosine kinase-1-placental growth factor ratio test to assess for preeclampsia and its severity. However, it may not be feasible to implement the most optimal screening protocol for preeclampsia in the first trimester which uses a combination of maternal characteristics, maternal biophysical and biochemical markers due to limitations in the access to uterine artery doppler ultrasound. There are inconsistent findings on how early in the second trimester the fms-like tyrosine kinase-1-placental growth factor ratio begins to provide useful information in preeclampsia prediction. This study aimed to assess the accuracy of (1) a combination of maternal characteristics, maternal serum pregnancy-associated plasma protein A, and placental growth factor in the screening for preeclampsia in the first trimester; and (2) placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio in the prediction of preeclampsia in the early second trimester. This retrospective case-control study used frozen residual blood samples from women who had aneuploidy screening and delivered at a tertiary center. The case group included pregnancies with gestational hypertension or preeclampsia (further classified as early-onset [birth at <34 weeks' gestation] and preterm preeclampsia [birth at <37 weeks' gestation]). Each case was matched with 3 control pregnancies by date of blood sample draw, gestational age at first blood sample draw, maternal age, maternal ethnicity, type of multiple-marker screening, and amount of residual sample. Mann-Whitney U tests were used to assess the associations between serum markers and the risk of preeclampsia. Logistic regressions were used to assess if the risk of preeclampsia can be predicted using a combination of maternal characteristics and serum markers. The case group included 146 preeclampsia and 295 gestational hypertension cases. Compared with the controls, preeclampsia cases had significantly lower first-trimester pregnancy-associated plasma protein A and placental growth factor. At a 20% false-positive rate, 71% of early-onset and 58% of preterm preeclampsia cases can be predicted using maternal characteristics, pregnancy-associated plasma protein A, and placental growth factor. Preeclampsia cases had lower second-trimester placental growth factor and a higher soluble fms-like tyrosine kinase-1-placental growth factor ratio. At a 10% false-positive rate, 80% and 53% of early-onset preeclampsia can be predicted using maternal characteristics and placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio, respectively. The current first-trimester aneuploidy screening programs may be expanded to identify women at increased risk of developing preeclampsia. Early in the second trimester, placental growth factor alone provided better prediction for preeclampsia compared with the soluble fms-like tyrosine kinase-1-placental growth factor ratio.

Does endometrial thickness affect birth weight and serum levels of pregnancy-associated plasma protein-A in frozen cycles?

ObjectiveTo investigate whether endometrial thickness (EMT) affects birth weight and maternal serum pregnancy-associated plasma protein-A (PAPP-A) level in singleton pregnancies following frozen–thawed blastocyst transfer (FET). MethodsThis retrospective study included women who underwent first-trimester combined screening for aneuploidy after FET, and subsequently delivered a singleton live birth after 24 weeks of gestation at a private in-vitro fertilization centre. The subjects were stratified into three groups based on EMT percentiles: <7.7 mm (<10th percentile), 7.7–12 mm (10–90th percentile), and > 12 mm (>90th percentile). Multi-variable linear regression analysis was undertaken to identify the association between birth weight and EMT after adjusting for variables with p < 0.1 on univariate analysis. ResultsIn total, 560 women met the inclusion criteria. Mean (±standard deviation) birth weight was 3127 ± 783 g in those with EMT < 7.7 mm, 3225 ± 644 g in those with EMT 7.7–12 mm, and 3256 ± 599 g in those with EMT > 12 mm (p = 0.577). Mean PAPP-A and PAPP-A < 0.5 rates were similar in the three groups. On multi-variate analysis, maternal serum PAPP-A was found to be a significant predictor of birth weight (p = 0.013), but EMT was not found to be predictive of birth weight on univariate or multi-variate analysis. ConclusionThis study provided a new angle to evaluate the association between EMT and neonatal birth weight by analysing this association along with maternal serum PAPP-A as a marker for placental function, suggesting that EMT is not an independent factor for neonatal birth weight.

Association of maternal risk factors with fetal aneuploidy and the accuracy of prenatal aneuploidy screening: a correlation analysis based on 12,186 karyotype reports

BackgroundNIPT is becoming increasingly important as its use becomes more widespread in China. More details are urgently needed on the correlation between maternal risk factors and fetal aneuploidy, and how these factors affect the accuracy of prenatal aneuploidy screening.MethodsInformation on the pregnant women was collected, including maternal age, gestational age, specific medical history and results of prenatal aneuploidy screening. Additionally, the OR, validity and predictive value were also calculated.ResultsA total of 12,186 analysable karyotype reports were collected with 372 (3.05%) fetal aneuploidies, including 161 (1.32%) T21, 81 (0.66%) T18, 41 (0.34%) T13 and 89 (0.73%) SCAs. The OR was highest for maternal age less than 20 years (6.65), followed by over 40 years (3.59) and 35–39 years (2.48). T13 (16.95) and T18 (9.40) were more frequent in the over-40 group (P < 0.01); T13 (3.62/5.76) and SCAs (2.49/3.95) in the 35–39 group (P < 0.01). Cases with a history of fetal malformation had the highest OR (35.94), followed by RSA (13.08): the former was more likely to have T13 (50.65) (P < 0.01) and the latter more likely to have T18 (20.50) (P < 0.01). The sensitivity of primary screening was 73.24% and the NPV was 98.23%. The TPR for NIPT was 100.00% and the respective PPVs for T21, T18, T13 and SCAs were 89.92, 69.77, 53.49 and 43.24%, respectively. The accuracy of NIPT increased with increasing gestational age (0.81). In contrast, the accuracy of NIPT decreased with maternal age (1.12) and IVF-ET history (4.15).Conclusions①Pregnant patients with maternal age below 20 years had higher risk of aneuploidy, especially in T13; ②A history of fetal malformations is more risky than RSA, with the former more likely to have T13 and the latter more likely to have T18; ③Primary screening essentially achieves the goal of identifying a normal karyotype, and NIPT can accurately screen for fetal aneuploidy; ④A number of maternal risk factors may influence the accuracy of NIPT diagnosis, including older age, premature testing, or a history of IVF-ET. In conclusion, this study provides a reliable theoretical basis for optimizing prenatal aneuploidy screening strategies and improving population quality.

Cost-effectiveness of ultrasound before non-invasive prenatal screening for fetal aneuploidy.

To determine the cost-effectiveness of first-trimester ultrasound before fetal aneuploidy screening with cell-free DNA (cfDNA) compared with screening by cfDNA alone. A decision analytic model was constructed for 400 000 pregnant individuals with advanced maternal age who desired first-trimester aneuploidy screening with cfDNA in the USA, to compare two screening strategies: (1) cfDNA only and (2) ultrasound performed within 4 weeks before cfDNA. Input parameters included probability of fetal aneuploidy, cfDNA performance, desire for diagnostic testing, pregnancy outcomes, and pregnancy and lifetime costs and utilities. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), in terms of cost in 2020 US dollars (USD) per quality-adjusted life year (QALY) gained. Secondary outcomes included procedure-related loss, pregnancy termination, live birth with aneuploidy, live birth with structural anomaly and stillbirth. Discounting was performed at 3% per year with an estimated maternal lifespan of 81 years starting at the age of 35 years. One-way, multiway and Monte Carlo probabilistic sensitivity analyses were performed. All base-case estimates and ranges of uncertainty were derived from the literature. The willingness-to-pay threshold was set at 100 000 USD per QALY. In the base-case analysis, ultrasound before cfDNA screening was more cost-effective than cfDNA screening without pretest ultrasound, with an ICER of 12 588 USD and higher net monetary benefit (24 241 vs 20 466). The strategy involving ultrasound before cfDNA was more costly by 544 USD but also more effective (by 0.04 QALY) compared with cfDNA alone. Base-case results were robust in sensitivity analyses with the strategy involving ultrasound before cfDNA always remaining the most cost-effective approach with the highest net monetary benefit. First-trimester ultrasound before cfDNA is a more cost-effective strategy for non-invasive prenatal aneuploidy screening compared with cfDNA alone. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Timing of Diagnosis of Fetal Structural Abnormalities After the Introduction of Universal Cell-Free DNA in the Absence of First-Trimester Anatomical Screening

ABSTRACT Cell-free DNA (cfDNA) screens are now widely used for trisomy 21, 18, and 13 (and less often for sex-chromosome aberrations). In 2017, the Netherlands became the first country to implement genome-wide cfDNA as a first-tier screening test for chromosomal abnormalities. The use of this test for first-trimester screening subsequently increased from 32% to 45%, with 2% of women still choosing to have the combined test. Although the official purpose of these tests is for aneuploidy screening, studies demonstrate that at least one-fourth of structural abnormalities in fetuses can be detected during nuchal translucency (NT) measurement. Whether the routine addition of first-trimester anatomy screening (FTAS) would be effective in detecting severe fetal structural anomalies with low rates of false-positive results was felt to be important to address, to determine whether this should be an integral component of prenatal screening program. This study aimed to determine the gestational age at which fetal anomalies were detected and which anomalies detected by second-trimester anatomical screening could have theoretically been diagnosed via FTAS had this been performed on all women in the cohort. The data for this retrospective observational study were collected from pregnant women referred to the University Medical Center of Groningen Fetal Medicine Unit from 2017 through 2020. Women in the cohort were referred based on suspicion of fetal structural abnormalities following a dating ultrasound, or first- or second-trimester anatomy survey. First-trimester anatomy surveys were performed only in women with high-risk indications, including monochorionic twin pregnancy (or greater multiple pregnancy), first-degree relative of the fetus with structural abnormalities, more than 1 more distant relative with similar abnormalities, preexisting diabetes mellitus or first-trimester diagnosis of diabetes mellitus, high-titer thyroid-stimulating hormone receptor antibodies, or high radiation exposure of &gt;0.50 Gy. In the study, all information was collected regarding additional examinations, invasive testing, and pregnancy outcomes, including postpartum follow-up to confirm the diagnosis. Cases with an abnormal cfDNA result or increased risk for aneuploidy based on serum screening were not included, nor were “soft markers” for aneuploidy or variations of normal anatomy such as persistent left superior vena cava. In all, 547 pregnancies had second-trimester anomalies and were included in the analysis. A total of 13 pregnancies underwent FTAS, whereas the other 534 (97.6%) underwent only the dating ultrasound scan and second-trimester anatomy scanning. Average maternal age was 29 years, with a median body mass index of 25.1 kg/m2, and the mean gestational age at the time of the anatomical survey of 21.4 weeks. Of the 13 pregnancies that underwent FTAS, anomalies were confirmed in 12 fetuses, whereas 1 had edema that resolved. Overall, 492 fetuses (92.1%) had structural anomalies that were confirmed, and analysis was done to determine whether these would have been diagnosable in the first trimester. In all, 66 (13.4%) were classified as “always detectable” in the first trimester, 303 (61.6%) as “sometimes detectable,” and 123 (25.0%) as “never detectable.” The mean gestational age at diagnosis was 22.8 weeks. Limitations of the study include its hypothetical classification of abnormalities as “always,” “sometimes,” and “never,” based on the literature. However, the authors concluded that the introduction of an early anatomical survey together with noninvasive screening for aneuploidies is appropriate based on these results.

First-Trimester Evaluation of Cleft Lip and Palate by A Novel Two-Dimensional Sonographic Technique: A Prospective Study.

The study aims to evaluate the value of the mandible transection head-side shifting method (MTHSM) by 2-dimensional sonography in the screening of fetal cleft lip and palate (CLP) during the nuchal translucency scans. A total of 7,336 fetuses enrolled for first-trimester aneuploidy screening were included in this prospective study. A sequential scanning approach from the mandible transection toward the head was used for the assessment of the palate in the midsagittal, axial, and coronal sections. Observe the continuity of the palatal line, upper alveolar ridge, and primary palate. All fetuses were followed by second-trimester scans and postnatal evaluation. A total of 18 cases of CLP were identified in the first trimester based on this method. Out of 18, 9 (50.0%) were unilateral CLP, 4 (22.2%) were bilateral CLP, and 5 (27.8%) were median CLP. There were no false-positive results found. Three were missed but confirmed in the second-trimester anomaly scan, including 2 cases of isolated cleft palate (CP) and one of isolated cleft lip (CL). Firsttrimester diagnosis of CLP using MTHSM had a sensitivity of 85.7%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 99.9%. The mandible transection head-side shifting method is feasible in assessing CLP at the time of routine first-trimester sonographic screening.

Abstract P2-03-14: Tumor-agnostic measurement of ctDNA levels in first line ER+, HER2- metastatic breast cancer patients as a marker for survival

Abstract INTRODUCTION: Circulating tumor cell (CTC) count and levels of circulating tumor DNA (ctDNA) have proven their individual prognostic value in metastatic breast cancer (MBC). Whereas CTCs can be quantified by enumeration, levels of ctDNA are often expressed as the variant allele frequency of the dominant mutation. The modified fast aneuploidy screening test-sequencing system (mFAST-SeqS) estimates ctDNA-load by measuring chromosomal aneuploidy instead of mutations. The mFAST-SeqS method is cheap and provides a comprehensive overview of the tumor genome without prior knowledge on genomic tumor aberrations. Previously, we showed in a small MBC cohort (n=50), heterogeneous with regard to subtype and line of treatment, that the mFAST-SeqS-derived genome-wide aneuploidy score (GWA-score) was an independent prognostic biomarker (1). Our current aim was to provide evidence for the prognostic value of GWA-score in a homogeneous cohort of estrogen receptor positive (ER+), HER2 negative (HER2-) MBC patients, starting first line treatment with an aromatase inhibitor. MATERIALS &amp; METHODS: CTCs were enumerated using the CellSearch-system (Menarini) and screened for ctDNA fraction using mFAST-SeqS in ER+, HER2- MBC patients, starting with first line aromatase inhibitors. CTC-count was divided into high (CTChigh) and low (CTClow) using the validated cut-off of 5 CTCs/7.5 ml blood; similarly GWA-score was divided in high (GWAhigh)and low (GWAlow) based on the previously described cut-off of 5 (2). PFS and OS were estimated using Kaplan-Meier. Cox regression was used for uni- and multivariable analysis. RESULTS: One hundred and thirty-four patients were included in this analysis. Mean age was 68 (range 40-90). Median follow up was 26 months. Sixty-five samples had both scores low and 30 both high, 25 samples were CTChigh/GWAlow and 14 were CTClow/GWAhigh. PFS and OS were not significantly different between CTChigh versus CTClow groups (p=0.07 and p=0.26, median PFS 15 vs 24 months, median OS 45 vs 49 months). However, PFS and OS were significantly different between GWAhigh versus GWAlow groups (p &amp;lt; 0.01 for both, median PFS 11 vs 24 months, median OS 31 vs 51 months). In multivariate analysis, GWA-score was a significant prognostic factor for both PFS and OS while presence of visceral disease was also prognostic for OS (table 1). CONCLUSIONS: In patients treated with aromatase inhibitors in the first line of treatment, GWA-score was an independent prognostic marker for a worse PFS and OS and may have added value beyond CTC-count. 1. Verschoor, N., et al., Abstract P2-01-17: Circulating tumor cell count and levels of circulating tumor DNA are complementary prognostic biomarkers in metastatic breast cancer - A pilot study. Cancer Research, 2022. 82(4_Supplement): p. P2-01-17-P2-01-17. 2. Belic, J., et al., mFast-SeqS as a Monitoring and Pre-screening Tool for Tumor-Specific Aneuploidy in Plasma DNA. Adv Exp Med Biol, 2016. 924: p. 147-155. Table 1: Uni- and multivariate Cox regression for PFS and OS Citation Format: Noortje Verschoor, Jaco Kraan, Vanja de Weerd, Ngoc M Van, Agnes Jager, Stefan Sleijfer, John WM Martens, Saskia M Wilting. Tumor-agnostic measurement of ctDNA levels in first line ER+, HER2- metastatic breast cancer patients as a marker for survival [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-14.

The effects of dydrogesterone treatment on first-trimester aneuploidy screening markers and nuchal translucency in women with threatened miscarriage.

To evaluate the effects of dydrogesterone treatment on first-trimester aneuploidy screening markers and nuchal translucency (NT) in women with threatened miscarriage. This study is an prospective case-control study. One hundred seven pregnant women who applied for the first-trimester screening test at 11-14th weeks of gestation were included in the study. The study group consisted of 53 pregnant women using oral dydrogesterone due to the threat of miscarriage for at least 2 weeks and without vaginal bleeding for the last 72 h at the time of enrollment. The control group was composed of 54 healty pregnant women. Fetal Crown-rump length (CRL), NT, pregnancy-associated plasma protein-A (PAP-A) level, and free beta-human chorionic gonadotropin (free B-hCG) levels of the patients were measured. One hundred seven patients included in the study, 54 (50.46%) were in the control group, and 53 (49.54%) were in the study group using dydrogesterone. Age, body mass index, gravida, parity and abortion numbers, gestational weeks, and CRL values of the two groups were congruent. In the comparison-free B-hCG, PAPP-A and NT values of both groups, no statistically significant difference was found between the two groups in terms of first-trimester test results and NT (p<0.05). The use of dydrogesterone in first-trimester pregnancies does not affect first-trimester screening tests and nuchal translucency.

Body Stalk Anomaly Complicated by Ectopia Cordis: First-Trimester Diagnosis of Two Cases Using 2- and 3-Dimensional Sonography

Body stalk anomaly is a severe defect of the abdominal wall, characterized by the evisceration of abdominal organs and, in more severe cases, thoracic organs as well. The most serious condition in a body stalk anomaly may be complicated by ectopia cordis, an abnormal location of the heart outside the thorax. The aim of this scientific work is to describe our experience with the prenatal diagnosis of ectopia cordis as part of the first-trimester sonographic screening for aneuploidy. We report two cases of body stalk anomalies complicated by ectopia cordis. The first case was identified during a first ultrasound examination at 9 weeks of gestation. The second was identified during an ultrasound examination at 13 weeks of gestation. Both of these cases were diagnosed using high-quality 2- and 3-dimensional ultrasonographic images obtained by the Realistic Vue and Crystal Vue techniques. The chorionic villus sampling showed that the fetal karyotype and CGH-array were both normal. In our clinical case reports, the patients, immediately after the diagnosis of a body stalk anomaly complicated by ectopia cordis, opted for the termination of pregnancies. Performing an early diagnosis of a body stalk anomaly that is complicated by ectopia cordis is desirable, considering their poor prognoses. Most of the reported cases in the literature suggest that an early diagnosis can be made between 10 and 14 weeks of gestation. A combination of 2- and 3-dimensional sonography could allow an early diagnosis of body stalk anomalies complicated by ectopia cordis, particularly using new ultrasonographic techniques, the Realistic Vue and the Crystal Vue.

Clinical application and evaluation of health economics for non-invasive prenatal testing of fetuses in Tianjin

To assess the clinical efficacy and health economic value of non-invasive prenatal testing (NIPT) for the prenatal screening of common fetal chromosomal aneuploidies. 10 612 pregnant women from October 2017 to December 2019 presented at the antenatal screening clinic of the General Hospital of Tianjin Medical University were selected as the study subjects. Results of NIPT and invasive prenatal diagnosis and follow-up outcome for the 10 612 pregnant women were retrospectively analyzed and compared. Meanwhile, NIPT data for two periods were analyzed for assessing the health economic value of NIPT as the second- or first-tier screening strategy for the prenatal diagnosis of fetal trisomies 21, 18 and 13. The NIPT was successful in 10 528 (99.72%) subjects, with the sensitivity for fetal trisomies 21, 18 and 13 being 100%, 92.86% and 100%, and the positive predictive value (PPV) being 89.74%, 61.90% and 44.44%, respectively. The PPV of NIPT for sex chromosome aneuploidies was 34.21%. Except for one false negative case of trisomy 18, the negative predictive value for trisomy 21, trisomy 13 and other chromosomal abnormalities were 100%. For pregnant women with high risk by serological screening, advanced maternal age or abnormal ultrasound soft markers, NIPT has yielded a significantly increased high risk ratio. There was no statistical difference in the PPV of NIPT among pregnant women from each subgroup. NIPT would have higher health economic value as a second-tier screening until 2019, while compared to 2015 ~ 2017, its incremental cost-effectiveness ratio as a first-tier screening had declined clearly. The screening efficacy of NIPT for trisomies 21, 18 and 13 for a mixed population is significantly better than conventional serological screening, but it is relatively low for sex chromosomal abnormalities. NIPT can also be recommended for populations with relatively high risks along with detailed pre- and post-test genetic counselling. From the perspective of health economics, except for open neural tube defects, it is possible for NIPT to replace the conventional serological screening in the future as its cost continues to decrease.

Organ-specific learning curves of sonographers performing first-trimester anatomical screening and impact of score-based evaluation on ultrasound image quality.

First-trimester anatomical screening (FTAS) by ultrasound has been introduced in many countries as screening for aneuploidies, but also as early screening for fetal structural abnormalities. While a lot of emphasis has been put on the detection rates of FTAS, little is known about the performance of quality control programs and the sonographers' learning curve for FTAS. The aims of the study were to evaluate the performance of a score-based quality control system for the FTAS and to assess the learning curves of sonographers by evaluating the images of the anatomical planes that were part of the FTAS protocol. Between 2012-2015, pregnant women opting for the combined test in the North-Netherlands were also invited to participate in a prospective cohort study extending the ultrasound investigation to include a first-trimester ultrasound performed according to a protocol. All anatomical planes included in the protocol were documented by pictures stored for each examination in logbooks. The logbooks of six sonographers were independently assessed by two fetal medicine experts. For each sonographer, logbooks of examination 25-50-75 and 100 plus four additional randomly selected logbooks were scored for correct visualization of 12 organ-system planes. A plane specific score of at least 70% was considered sufficient. The intra-class correlation coefficient (ICC), was used to measure inter-assessor agreement for the cut-off scores. Organ-specific learning curves were defined by single-cumulative sum (CUSUM) analysis. Sixty-four logbooks were assessed. Mean duration of the scan was 22 ± 6 minutes and mean gestational age was 12+6 weeks. In total 57% of the logbooks graded as sufficient. Most sufficient scores were obtained for the fetal skull (88%) and brain (70%), while the lowest scores were for the face (29%) and spine (38%). Five sonographers showed a learning curve for the skull and the stomach, four for the brain and limbs, three for the bladder and kidneys, two for the diaphragm and abdominal wall and one for the heart and spine and none for the face and neck. Learning curves for FTAS differ per organ system and per sonographer. Although score-based evaluation can validly assess image quality, more dynamic approaches may better reflect clinical performance.

Understanding genetic screening for aneuploidy in pregnant women

Understanding genetic screening for aneuploidy in pregnant women

Aneuploidy screening after preimplantation genetic testing: a national survey of physician knowledge and practice.

To assess the knowledge of generalist OB/GYN providers on aneuploidy screening recommendations for patients who utilized preimplantation genetic testing, and to survey providers' current practice habits. A 12-question survey was distributed by email to OB/GYN physicians in the USA. Demographic information was also collected. A total of 178 survey responses were included for analysis. Sixty-seven percent correctly identified the current ACOG recommendation to offer additional aneuploidy screening/invasive diagnostic testing regardless of PGT status, and 66% said their practice is consistent with this recommendation. Ninety-one percent of responders correctly answered that in vitro fertilization does not always include PGT and 63% of responders were able to correctly identify the 3 available types of PGT. Thirty-three percent (n = 58) were attending physicians, and 67% (n = 120) were resident physicians. Most participants (81%, n = 145) stated they have been in practice 0-9 years, and the remaining 19% (n = 33) stated they have been in practice ≥ 10 years. Significant knowledge gaps of PGT and aneuploidy screening recommendations after PGT exist among generalist OB/GYN physicians. Efforts should be made to educate providers on the importance of offering aneuploidy screening and diagnostic testing to patients who utilized PGT to improve patient care.

Legal Limits Relaxed: Time to Look at Other Barriers Faced by Women Seeking Termination of Pregnancy for Fetal Anomalies.

Introduction Advancements in prenatal diagnostic techniques have led to an increase in demand for termination of pregnancy for fetal anomalies (TOPFA). While relaxation in the legal gestational age limits across various countries relieves an important barrier, there is a need to identify the reasons that lead to delays in seeking abortion for fetal anomalies, because abortion-related complications increase with gestational age. Methods In this hospital-based qualitative study, antenatal women referred to a tertiary care institute in North India because of major fetal anomalieswere explained about the study. Those women who fulfilled the inclusion criteria were recruited after taking consent. Details of antenatal care and prenatal tests were recorded. An in-depth inquiry was made into the reasons for the delay in prenatal tests, the delay in the decision for abortion, and specific problems that they faced in seeking TOPFA. Results Out of 80 women who met the inclusion criteria and consented to participate, more than 75%had received antenatal care in public healthcare facilities. Less than 50% of women received folic acid in the first trimester while 26% had first contact with healthcare facilities in the second trimester. Only 21 women underwent screening for common aneuploidies. Second-trimester anomaly scan was delayed in 35 women due to women-centered reasons (n = 17) or provider-centered (n = 19) reasons. Only 37.5% of women were counseled about fetal anomalies by their primary care provider. Owing to delay at multiple levels, 40 women (50%) could receive counseling about fetal abnormality for the first time after 20 weeks. These women could not be offered abortion because this study was carried out before theamendments in the Medical Termination of Pregnancy Act in India. The older act allowed abortion up to 20 weeks of gestation. Seventeen women could obtain permission for an abortion from a court of law. Arrangements for travel and stayand dependence on family members were the main problems faced by women seeking TOPFA. Conclusions Delay in diagnosis of a fetal anomaly due to delay in seeking antenatal care, irregular follow-up, and lack of pre-test counseling are the major reasons for the delay in the decision for abortion. This is further compounded by inadequate post-test counseling. Lack of awareness, failure or delay in counseling, need to travel to another facility for abortion, dependence on family members, and financial issues are the major barriers.