First-trimester Risk Assessment Research Articles

Decoding 22q11.2: prenatal profiling and first-trimester risk assessment in Danish nationwide cohort.

To examine the distribution of nuchal translucency thickness (NT), free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and β-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated. We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). β-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and β-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Which first-trimester risk assessment method for preeclampsia is most suitable? A model–based impact study

Low-dose aspirin treatment reduces the risk of preeclampsia among high-risk pregnant women. Internationally, several first-trimester risk-calculation methods are applied. This study aimed to assess the costs and benefits of different first-trimester preeclampsia risk estimation algorithms: EXPECT (an algorithmic prediction model based on maternal characteristics), National Institute for Health and Care Excellence (a checklist of risk factors), and the Fetal Medicine Foundation (a prediction model using additional uterine artery Doppler measurement and laboratory testing) models, coupled with low-dose aspirin treatment, in comparison with no risk assessment. We constructed a decision analytical model estimating the number of cases of preeclampsia with each strategy and the costs of risk assessment for preeclampsia and early aspirin treatment, expressed in euros (€) in a hypothetical population of 100,000 women. We performed 1-way sensitivity analyses to assess the impact of adherence rates on model outcomes. Application of the EXPECT, National Institute for Health and Care Excellence, and Fetal Medicine Foundation models results in respectively 1.98%, 2.55%, and 1.90% of the women developing preeclampsia, as opposed to 3.00% of women in the case of no risk assessment. Overall, the net financial benefits of the EXPECT, National Institute for Health and Care Excellence, and Fetal Medicine Foundation models relative to no risk assessment are €144, €43, and €38 per patient, respectively. The respective percentages of women receiving aspirin treatment are 18.6%, 10.2%, and 6.0% for the 3 risk assessment methods. The EXPECT and Fetal Medicine Foundation model are comparable with regard to numbers of prevented preeclampsia cases, and both are superior to the National Institute for Health and Care Excellence model and to no risk assessment. EXPECT is less resource-demanding and results in the highest cost savings, but also requires the highest number of women to be treated with aspirin. When deciding which strategy is preferable, cost savings and easier use have to be weighed against the degree of overtreatment, although low-dose aspirin has no clear disadvantages during pregnancy.

Atypicality index: avoiding false reassurance in prenatal screening.

To demonstrate the application of the atypicality index as an adjunct to first-trimester risk assessment for major trisomies by the combined test. This was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first-trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index. In pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnancies with a low risk for trisomies and atypicality index of ≥ 99%, the incidence of adverse outcome was 5.1 (95% CI, 3.4-7.6) times higher compared with that in low-risk pregnancies with a typical measurement profile, reflected by an atypicality index of < 80%. Similarly, in high-risk pregnancies, the incidence of adverse outcome was 7.9 (95% CI, 4.4-14.5) times higher in those with an atypicality index of ≥ 99% compared to those with an atypicality index of < 80%. Using individual profile plots, we were able to demonstrate a transparent and intuitive method for visualization of multiple variables, which can help interpret the individual combination of measurements and level of atypicality. In pregnancies undergoing first-trimester combined screening and classified as being at low risk for major trisomies, profiles that are typical of pregnancies with normal outcome provide additional reassurance, whereas those with an atypical profile may warrant further investigation. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Prenatally detected isolated ventricular septum defects and the association with chromosomal aberrations-A nationwide register-based study from Denmark.

To evaluate the association between prenatally detected isolated ventricular septum defects (VSDs) and chromosomal aberrations in a nationwide study in Denmark. Nationwide, register-based study with prospectively collected data including all singleton pregnancies from 2014-2018. From the Danish Fetal Medicine Database, we retrieved data on maternal characteristics, first-trimester biomarkers, pre- and postnatal diagnoses, genetic test results, and pregnancy outcomes. VSDs were considered isolated in the absence of other malformations or soft markers, and with a low first-trimester risk assessment for trisomies 21, 18 and 13. All cases of an isolated VSD with a chromosomal anomaly were audited. The genetic tests included karyotyping and chromosomal microarray. We retrieved data on 292 108 singleton pregnancies; 323 registered with a prenatally detected VSD and 697 with a VSD detected postnatally (incidence of 0.35%). Only 1/153 (0.7%, 95% CI 0.02;3.6%) of the isolated prenatally detected VSDs had an abnormal genetic test result (del (8)(q23.1)). Moreover, they had a lower free β-hCG MoM (0.9 MoM vs 0.99 MoM, P = 0.02), and were more likely born small for gestational age (SGA), defined as birthweight 2 or more SD below the mean, compared with the control population (5.2% vs 2.5%, P = 0.03). We found a prevalence of chromosomal aberrations of 0.7% in fetuses with a prenatally detected isolated VSD. Moreover, we found an association between isolated VSDs and a larger proportion being born SGA.

Impact of new definitions of pre-eclampsia on incidence andperformance of first-trimester screening.

The traditional definition of pre-eclampsia (PE) is based on the development of hypertension and proteinuria. This has been revised recently to include cases without proteinuria but with evidence of renal, hepatic or hematological dysfunction. The aim of this study was to examine the impact of new definitions of PE on, first, the incidence and severity of the disease and, second, the performance of the competing-risks model for first-trimester assessment of risk for PE. This was a retrospective study of 66 964 singleton pregnancies that were classified as having PE, gestational hypertension (GH) or no PE or GH, according to the traditional criteria of the International Society for the Study of Hypertension in Pregnancy (ISSHP-old), which defines PE as the presence of both hypertension and proteinuria. We reviewed the records of pregnancies with GH, and those cases with high creatinine or liver enzymes or low platelet count were reclassified as having PE, according to the new criteria of ISSHP (ISSHP-new) and the new criteria of the American College of Obstetricians and Gynecologists (ACOG). The groups of PE according to the traditional and new criteria were compared for, first, gestational age at delivery, birth-weight percentile and incidence of a small-for-gestational-age (SGA) neonate with birth weight < 10th percentile and perinatal death, and, second, the predictive performance for preterm PE of the competing-risks model based on the combination of maternal risk factors, uterine artery pulsatility index, mean arterial pressure and serum placental growth factor at 11-13 weeks' gestation (triple test). According to ISSHP-old, 1870 (2.8%) cases had PE, 2182 (3.3%) had GH and 62 912 (94.0%) had no PE or GH. The incidence of PE according to ACOG was 3.0% (2029/66 964) and ISSHP-new was 3.4% (2301/66 964). Median gestational age at delivery in the extra cases of PE according to ACOG (difference, 1.3 weeks; 95% CI, 0.71-1.71 weeks) and in the extra cases of PE according to ISSHP-new (difference, 1.5 weeks; 95% CI, 1.29-1.71 weeks) was higher than in cases with PE according to ISSHP-old (38.4 weeks). The incidence of a SGA neonate in the extra cases of PE according to ACOG (relative risk, 0.57; 95% CI, 0.42-0.79) and in the extra cases of PE according to ISSHP-new (relative risk, 0.52; 95% CI, 0.42-0.65) was lower than in the cases of PE according to ISSHP-old (33.64%). In first-trimester screening for preterm PE by the triple test, the detection rate, at a 10% false-positive rate, was 75.9% (95% CI, 70.8-80.6%) for ISSHP-old, 74.3% (95% CI, 69.2-79.0%) for ACOG and 74.0% (95% CI, 68.9-78.6%) for ISSHP-new. The new definitions of PE resulted in, first, an increase in pregnancies classified as having PE but the additional cases had milder disease, and, second, a non-significant decrease in the performance of first-trimester screening for PE. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Is there a future for cell-free fetal dna tests in screening for preeclampsia?

CffDNA screening is a powerful diagnostic tool in the prenatal diagnosis algorithm for chromosomal abnormalities. With detailed ultrasound examination as the mainstay of first-trimester risk assessment, cffDNA has been shown to be superior to first-trimester combined screening (FTCS) in false-positive rates for trisomy 21 detection. In light of the growing interest in cffDNA testing and the possibility of it replacing first-trimester biochemistry, we decided to investigate the usefulness of cffDNA tests in early-pregnancy risk assessment for preeclampsia (PE). The aim of this review paper was to evaluate clinical application of first-trimester cfDNA in predicting PE, as well as to investigate its possible use in first-trimester PE screening enhancement, also in cases where biochemistry is not performed.

First-trimester risk assessment based on ultrasound and cell-free DNA vs combined screening: a randomized controlled trial.

This was a randomized controlled trial to compare risk assessment by first-trimester combined screening (FTCS) with an approach that combines a detailed ultrasound examination at 11-13 weeks' gestation and cell-free DNA (cfDNA) analysis. Pregnant women with a normal first-trimester ultrasound examination at 11-13 weeks' gestation (fetal nuchal translucency (NT)≤ 3.5 mm and no fetal defects) were randomized into one of two groups. In the first group, risk of aneuploidy was assessed using FTCS based on the most recent UK Fetal Medicine Foundation algorithm. In the second group, risk assessment was based on ultrasound findings and cfDNA analysis. An additional tube of blood was collected for FTCS in case the cfDNA analysis was uninformative. Primary outcome was false-positive rate in screening for trisomy 21. A case was considered false positive if the karyotype was not trisomy 21 and if the risk for trisomy 21 was >1:100, irrespective of the method of risk calculation. Results were compared using 95% CIs using the Clopper-Pearson method. Between October 2015 and December 2016, 1518 women with singleton pregnancy underwent first-trimester screening. Thirty-one (2.0%) pregnancies were not eligible for randomization due to increased NT (> 3.5 mm) and/or fetal defect. After exclusion of women who declined randomization (n= 87) and cases of fetal death and loss to follow-up (n= 24), 688 pregnancies were randomized into the FTCS arm and 688 into the ultrasound + cfDNA analysis arm. There were no differences in maternal and gestational age, maternal weight and BMI, ethnicity, use of assisted reproduction and cigarette smoking between the two arms. In the ultrasound + cfDNA analysis arm, median risk for trisomy 21 was 1 in 10 000. None of the cases had a risk above 1: 100 (95% CI, 0.0-0.5%). In the FTCS arm, the median risk for trisomy 21 was 1 in 3787 and in 17 cases, the risk was higher than 1:100, which corresponds to 2.5% (95% CI, 1.5-3.9%) of the FTCS study-arm population. Our study has shown that first-trimester risk assessment for trisomy 21 that includes a detailed ultrasound examination as well as NT measurement and is followed by cfDNA testing is associated with a significant reduction in the false-positive rate compared with FTCS. This approach obviates the need for maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A in screening for fetal aneuploidy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Positive view and increased likely uptake of follow-up testing with analysis of cell-free fetal DNA as alternative to invasive testing among Danish pregnant women.

The aim of this study was to investigate the attitude (view, likely uptake and preferred strategy) towards cell-free fetal DNA (cfDNA) testing among pregnant women before a first-trimester risk assessment for trisomy 21 (unselected women) and after obtaining a high risk. Unselected and high-risk women attending first-trimester screening (Rigshospitalet, Copenhagen University Hospital) were invited to fill out the questionnaire Antenatal testing for Down syndrome as an online survey. The survey included 203 unselected and 50 high-risk women (response rates of 74.8% and 84.7%, respectively). Nearly all considered cfDNA testing a positive development in antenatal care, and 97.2% would like it to be offered. Offering cfDNA testing as an alternative to invasive testing would increase the uptake of follow-up testing compared with invasive testing alone (98.8% vs. 90.7%, p<0.001). Women who would only accept follow up by cfDNA testing were more likely to continue an affected pregnancy (30.0% vs. 3.6%, p<0.001) or have doubts about termination (50.0% vs. 32.1%, p<0.001). Offering cfDNA testing would likely increase the uptake of follow-up testing without a corresponding rise in the termination rate of affected fetuses as some women test for information only. However, both unselected and high-risk women had overwhelmingly positive views underlining attention to avoid routinization.

Non-invasive prenatal cell-free fetal DNA testing for down syndrome and other chromosomal abnormalities

Background: Chorionic villus sampling and amniocentesis as definitive diagnostic procedures represent a gold standard for prenatal diagnosis of chromosomal abnormalities. The methods are invasive and lead to a miscarriage and fetal loss in approximately 0.5–1 %. Non-invasive prenatal DNA testing (NIPT) is based on the analysis of cell-free fetal DNA from maternal blood. It represents a highly accurate screening test for detecting the most common fetal chromosomal abnormalities. In our study we present the results of NIPT testing in the Diagnostic Center Strah, Slovenia, over the last 3 years.Methods: In our study, 123 pregnant women from 11th to 18th week of pregnancy were included. All of them had First trimester assessment of risk for trisomy 21, done before NIPT testing.Results: 5 of total 6 high-risk NIPT cases (including 3 cases of Down syndrome and 2 cases of Klinefelter’s syndrome) were confirmed by fetal karyotyping. One case–Edwards syndrome was false positive. Patau syndrome, triple X syndrome or Turner syndrome were not observed in any of the cases. Furthermore, there were no false negative cases reported. In general, NIPT testing had 100 % sensitivity (95 % confidence interval: 46.29 %–100.00 %) and 98.95 % specificity (95 % confidence interval: 93.44 %–99.95 %). In determining Down syndrome alone, specificity (95 % confidence interval: 95.25 %- 100.00 %) and sensitivity (95 % confidence interval: 31.00 %–100.00 %) turned out to be 100 %. In 2015, the average turnaround time for analysis was 8.3 days from the day when the sample was taken. Repeated blood sampling was required in 2 cases (redraw rate = 1.6 %).Conclusions: Our results confirm that NIPT represents a fast, safe and highly accurate advanced screening test for most common chromosomal abnormalities. In current clinical practice, NIPT would significantly decrease the number of unnecessary invasive procedures and the rate of fetal loss caused by invasive diagnostics.

Committee Opinion Summary No. 638: First-Trimester Risk Assessment for Early-Onset Preeclampsia.

Hypertensive disorders with adverse sequelae (including preterm birth, maternal morbidity and mortality, and long-term risk of maternal cardiovascular disease) complicate 5-10% of pregnancies. Early identification of pregnant women at risk of developing early-onset preeclampsia would theoretically allow referral for more intensive surveillance or application of preventive therapies to reduce the risk of severe disease. In practice, however, the effectiveness of such triage would be hindered by the low positive predictive value for early-onset preeclampsia reported in the literature. In spite of the modest predictive value of first-trimester preeclampsia risk assessment and the lack of data demonstrating improved clinical outcomes, commercial tests are being marketed for the prediction of preeclampsia in the first trimester. Taking a detailed medical history to evaluate for risk factors is currently the best and only recommended screening approach for preeclampsia; it should remain the method of screening for preeclampsia until studies show that aspirin or other interventions reduce the incidence of preeclampsia for women at high risk based on first-trimester predictive tests.

Committee Opinion No. 638: First-Trimester Risk Assessment for Early-Onset Preeclampsia.

Hypertensive disorders with adverse sequelae (including preterm birth, maternal morbidity and mortality, and long-term risk of maternal cardiovascular disease) complicate 5-10% of pregnancies. Early identification of pregnant women at risk of developing early-onset preeclampsia would theoretically allow referral for more intensive surveillance or application of preventive therapies to reduce the risk of severe disease. In practice, however, the effectiveness of such triage would be hindered by the low positive predictive value for early-onset preeclampsia reported in the literature. In spite of the modest predictive value of first-trimester preeclampsia risk assessment and the lack of data demonstrating improved clinical outcomes, commercial tests are being marketed for the prediction of preeclampsia in the first trimester. Taking a detailed medical history to evaluate for risk factors is currently the best and only recommended screening approach for preeclampsia; it should remain the method of screening for preeclampsia until studies show that aspirin or other interventions reduce the incidence of preeclampsia for women at high risk based on first-trimester predictive tests.

802: Trends in timing of prenatal diagnosis and abortion for fetal chromosomal abnormalities

Major changes in risk assessment for chromosomal abnormalities include ACOG recommendations to offer first-trimester risk assessment to all patients in 2007, and the availability of NIPT in 2012. Our objective was to evaluate changes in timing of prenatal diagnosis and abortion for chromosomal abnormalities over the past 10-years.

Nearly a Third of Abnormalities Found After First-Trimester Screening Are Different Than Expected

Objective This study aimed to assess the efficacy of first-trimester aneuploidy screening in a single clinical setting. Methods Maternal age, nuchal translucency, and maternal serum levels of pregnancy-associated plasma protein A and free beta human chorionic gonadotrophin comprised first-trimester risk assessment for Down syndrome and trisomies 13/18. Means, screen positive rates, detection rates, and predictive values were calculated for Down syndrome and trisomies 13/18. Results Of the 23 329 first-trimester screenings, 6.3% were screen positive: 5.7% for Down syndrome only, 0.4% for trisomies 13/18 only, and 0.3% for Down syndrome and trisomies 13/18. An abnormal karyotype was present in 3.9% of screen positives for Down syndrome, 13.8% of screen positives for trisomies 13/18, and 45.9% of screen positives for both Down syndrome and trisomies 13/18. Of the 97 pregnancies found to have an abnormal karyotype, 29.9% had chromosome abnormalities other than trisomy 13, 18, or 21, with expected clinical outcomes ranging from likely benign to uniformly lethal. Conclusion As expected, first-trimester screening is effective for detecting aneuploidy for chromosomes 13, 18, and 21; however, a significant number of chromosomally abnormal pregnancies initially identified by first-trimester screening have a different karyotype. With the possible exception of 47,XYY and 45,X, the dataset suggested that these different chromosome complements were likely to be randomly distributed. Nevertheless, prior to diagnostic testing, prospective parents should be counseled concerning the possibility of a chromosome abnormality other than the trisomies 13, 18, or 21. © 2013 John Wiley & Sons, Ltd.

Nearly a third of abnormalities found after first‐trimester screening are different than expected:10‐year experience from a single center

This study aimed to assess the efficacy of first-trimester aneuploidy screening in a single clinical setting. Maternal age, nuchal translucency, and maternal serum levels of pregnancy-associated plasma protein A and free beta human chorionic gonadotrophin comprised first-trimester risk assessment for Down syndrome and trisomies 13/18. Means, screen positive rates, detection rates, and predictive values were calculated for Down syndrome and trisomies 13/18. Of the 23 329 first-trimester screenings, 6.3% were screen positive: 5.7% for Down syndrome only, 0.4% for trisomies 13/18 only, and 0.3% for Down syndrome and trisomies 13/18. An abnormal karyotype was present in 3.9% of screen positives for Down syndrome, 13.8% of screen positives for trisomies 13/18, and 45.9% of screen positives for both Down syndrome and trisomies 13/18. Of the 97 pregnancies found to have an abnormal karyotype, 29.9% had chromosome abnormalities other than trisomy 13, 18, or 21, with expected clinical outcomes ranging from likely benign to uniformly lethal. As expected, first-trimester screening is effective for detecting aneuploidy for chromosomes 13, 18, and 21; however, a significant number of chromosomally abnormal pregnancies initially identified by first-trimester screening have a different karyotype. With the possible exception of 47,XYY and 45,X, the dataset suggested that these different chromosome complements were likely to be randomly distributed. Nevertheless, prior to diagnostic testing, prospective parents should be counseled concerning the possibility of a chromosome abnormality other than the trisomies 13, 18, or 21.

First‐trimester screening for trisomy 21 in Denmark: implications for detection and birth rates of trisomy 18 and trisomy 13

In Denmark a new national guideline for prenatal screening and diagnosis was issued in 2004 according to which all pregnant women should be offered a first-trimester combined risk assessment for trisomy 21 (T21). The aim of this study was to investigate whether the new screening strategy for T21 has changed the gestational age at which trisomy 18 (T18) and trisomy 13 (T13) are diagnosed prenatally, and the number of infants born with T18 or T13. We collected from the Danish Cytogenetic Central Register information on all prenatal and postnatal chromosome analyses for T18 or T13, registered from 1997 to 2007. Information on first-trimester screening results was collected from each department of obstetrics and gynecology performing the nuchal translucency scans. The cut-off used for referral to invasive diagnostic testing for T21 and for T18/T13 was 1 : 300 and 1 : 150 at screening, respectively. In total, there were 435 cases with T18 and 168 cases with T13 between 1997 and 2007 in Denmark. The estimated incidence of T18 and T13 at the time of delivery was calculated as 2.5 and 1.6 per 10 000 deliveries, respectively. The number (proportion) of cases diagnosed before week 18 increased significantly, from 63 (59.4%) in 1997 and 1998 to 90 (80.4%) in 2006 and 2007 (P < 0.001). In addition, the number of T18 and T13 cases diagnosed prenatally after week 22 or postnatally decreased significantly, from 34 (32.1%) in 1997 and 1998 to seven (6.3%) in 2006 and 2007 (P < 0.0001). For women participating in first-trimester risk assessment in 2006 and 2007, the detection rate of T18 and T13 was 78.8% (95% CI, 71.0-86.7%). The number of T18 and T13 fetuses diagnosed before week 18 increased significantly after the introduction of a combined first-trimester screening strategy for T21 in Denmark. In addition, the total number of fetuses diagnosed late in pregnancy and infants born with T18 or T13 decreased significantly. The national detection rate for T18 and T13 in the first trimester is comparable with detection rates found in modeled datasets and other prospective studies.

Tricks for Obtaining a Nuchal Translucency Measurement on the Fetus in a Difficult Position

Received February 23, 2010, from the Departments of Radiology and Obstetrics and Gynecology, Brigham and Women’s Hospital (B.B., T.D.S., B.R.B.), and Departments of Radiology (B.R.B.) and Obstetrics and Gynecology (B.B., B.R.B.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts USA; and Diagnostic Ultrasound Associates, PC, Boston, Massachusetts USA (B.B., T.D.S., M.A.M., B.R.B.). Revision requested March 15, 2010. Revised manuscript accepted for publication March 17, 2010. Guest Editor: Alfred Z. Abuhamad, MD. Address correspondence to Bryann Bromley, MD, Diagnostic Ultrasound Associates, PC, 333 Longwood Ave, Suite 400, Boston, MA 02115 USA. E-mail: bbsono@aol.com Abbreviations NT, nuchal translucency creening for aneuploidy should be offered to all pregnant women.1 The demand for first-trimester sonography has been increasing rapidly as many women choose first-trimester risk assessment that involves the sonographic measurement of the fetal nuchal translucency (NT). Although most studies are easily accomplished using a standard transabdominal approach within a 20-minute window, not infrequently, the fetus may be positioned such that an adequate measurement of the NT is not possible. For example, Wax et al2 reported that they were able to obtain an NT measurement in only 80% of eligible women at the time of the first visit, despite allowing up to 30 to 40 minutes before abandoning the examination. Repeat scanning of the patients who returned resulted in an 86.6% success rate.2 The fetal position was consistently a factor in not being able to obtain an NT measurement, accounting for 67.3% of such cases.2 Other factors that prevent optimal measurement of the NT include a high maternal body mass index, as imaging in these patients generally requires more time and more return visits, ultimately resulting in a higher failure rate.3 We have developed 2 scanning techniques that enhance the chances that an adequate NT measurement will be obtained within the 20-minute time window. These techniques are based on approaching the uterus (and fetus) at right angles from the initial orientation, thus increasing the chances that the fetus will be imaged in the midsagittal view.

First-Trimester Aneuploidy Risk Assessment: The Impact of Comprehensive Counseling and Same-Day Results on Patient Satisfaction, Anxiety, and Knowledge

We evaluated the added benefit of a comprehensive counseling protocol for first-trimester aneuploidy risk assessment. We performed a prospective cohort study surveying patients referred for first-trimester aneuploidy risk assessment. We compared responses between women who underwent serum testing done in advance of their ultrasound such that their final risk assessment was given to them the same day as their ultrasound (comprehensive) versus women who underwent serum testing the same day as their ultrasound and who therefore received their final risk assessment later (standard). Response rate was 94.8%. The comprehensive group was significantly more likely to receive counseling in accordance with recommended American College of Obstetricians and Gynecologists (ACOG) guidelines, had significantly greater reduction in anxiety and increased satisfaction, and was more likely to report an increased understanding of their results. The comprehensive group scored significantly higher on test-style questions about aneuploidy risk assessment. Comprehensive aneuploidy risk assessment counseling including same-day results is associated with increased patient understanding and satisfaction, decreased anxiety, and increased adherence to ACOG guidelines.

Two‐stage first‐trimester screening for trisomy 21 by ultrasound assessment and biochemical testing

This study was carried out to examine the performance of a contingent policy in first-trimester screening for trisomy 21, in which the estimated risk was first derived by a combination of maternal age, fetal nuchal translucency (NT) thickness, presence/absence of the nasal bone, blood flow in the ductus venosus or flow across the tricuspid valve, and biochemical testing was carried out only in those who were found to have an intermediate risk. We also examined the performance of a policy in which the estimated risk was first derived by a combination of maternal age and biochemical testing, and ultrasound examination was carried out only in those with an intermediate risk. The data for this study were derived from prospective screening for trisomy 21 in singleton pregnancies, using, as markers, a combination of maternal age, fetal NT thickness and maternal-serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A), in a one-stop clinic for first-trimester assessment of risk at 11 + 0 to 13 + 6 weeks of gestation. Assessment of the fetal nasal bone, ductus venosus flow and tricuspid flow were also routinely performed by appropriately trained sonographers. The performance of different screening policies was examined. The study population consisted of 19 614 pregnancies with a normal karyotype or delivery of a phenotypically normal baby (euploid group) and 122 cases of trisomy 21. The best performance was achieved by a contingent policy in which first-stage screening was based on maternal age, fetal NT thickness and either tricuspid valve or ductus venosus blood flow, followed by biochemical testing only those with an intermediate risk, of 1 in 51 to 1 in 1000 (which constituted about 20% of the total). The performance of contingent screening in which first-stage testing relies on biochemistry was poorer than when first-stage screening was performed by ultrasound examination because, in order to achieve the same detection rate, the false-positive rate was twice as high. Effective first-trimester screening for trisomy 21 can be achieved by a contingent policy in which first-stage testing is based on ultrasound examination and second-stage biochemical testing is carried out in only 20% of the patients.

Ethical considerations in first-trimester Down syndrome risk assessment

First-trimester risk assessment has now become sophisticated and of increasing relevance and applicability to decision-making by pregnant woman about invasive diagnosis. Ethics is an essential dimension of understanding this relevance and applicability. This paper addresses the ethical dimensions of first-trimester risk assessment for trisomy 21. It is now well established in the ethics and law of the informed consent process that physicians are obligated to offer to patients all medically reasonable alternatives for managing the patient's condition. This disclosure should be guided by the reasonable person standard: the physician should provide clinically important information about the patient's condition or diagnosis, the medically reasonable alternatives for managing it, and the clinical benefits and risks of each such alternative. On the basis of the ethics of informed consent, we argue that routinely offering first-trimester risk assessment in centers qualified to provide it is ethically obligatory. We describe how pregnant women can be expected to respond to this offer. We then argue that routinely withholding the results of first-trimester risk assessment is ethically unjustified. The ethics of informed consent is an essential dimension of first-trimester risk assessment for trisomy 21.

The Ethics of Implementing First-trimester Risk Assessment

Abstract First trimester risk assessment has become a reliable screening tool for trisomy 21, replacing age-based risk assessment. On the basis of the ethical concept of the physician as fiduciary, the professional virtues of integrity and self-sacrifice, and the ethical principles of respect for autonomy, beneficence, and justice, we argue that the obstetrician has an ethical obligation to routinely offer pregnant women first trimester risk assessment in high quality centers. We then argue that both obstetricians and specialists in risk assessment have a strict ethical obligation to identify, responsibly manage, and disclose both economic and non-economic conflicts of interests, especially when they are hidden Ethics is an essential dimension of implementation of first trimester risk assessment for trisomy 21.