Nuchal Translucency Multiples Of The Median Research Articles

Increased Nuchal Translucency and Pregnancy Outcomes: A Tertiary Center Data

Aim: This study aimed to evaluate the pregnancy outcomes of patients who applied to our clinic between the 11th and 14th weeks of pregnancy and whose nuchal translucency (NT) measurement was ≥1.5 multiples of the median (MoM). Material and Methods: The study included 85 patients whose NT measurement was determined ≥1.5 MoM and pregnancy results were available. Demographic characteristics of the patients, prenatal invasive diagnostic test results, fetal anomaly screening, fetal echocardiography (ECHO) results, and neonatal and obstetric results were evaluated. Results: Abnormal karyotype was detected in 10.6% (n=9) of the patients. Trisomy 21 was the most common chromosomal anomaly. Fetal structural anomaly was detected in 29.4% (n=25) of the patients. A structural fetal anomaly was detected in 21% (n=13) of fetuses with normal karyotypes and 66.7% (n=6) of fetuses with abnormal karyotypes. Cardiac anomalies were found to be the most common anomalies with 9.7% (n=6) in patients with normal karyotype. NT and NT MoM values in patients with fetal structural (both p=0.001) or chromosomal anomalies (p=0.011, and p=0.019, respectively) were found significantly higher than those without. NT and NT MoM values in patients whose pregnancies resulted in fetal loss were found significantly higher than in patients who had a live birth (both p=0.001). Conclusion: Increasing NT or NT MoM values indicate an increase in the risk of chromosomal anomalies, structural anomalies, and poor pregnancy outcomes in the fetus. Fetal anomaly screening and fetal ECHO should be recommended in patients with increased NT, even if a normal karyotype is detected.

Reexamining the optimal nuchal translucency cutoff for diagnostic testing in the cell-free DNA and microarray era: results from the Victorian Perinatal Record Linkage study

The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at ≥3.0 mm, regardless of previous negative screening with noninvasive prenatal testing. This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities. This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y. Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of ≥3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of < 3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of ≥3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of <1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal translucency of ≥3.5 mm (147 of 491, 29.94%) than the group with a nuchal translucency of 3.0 to 3.4 mm (21 of 534, 3.93%) or a nuchal translucency of <3.0 mm (71 of 80,219, 0.09%) (P<.001). There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95% confidence interval, 2.51-6.22), 0.37% (95% confidence interval, 0.05-1.35), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.5 mm, 3.0 to 3.4 mm, and <3.0 mm, respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% confidence interval, 2.17-8.71), 2.53% (95% confidence interval, 1.36-4.29), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.0 MoM, 1.9 to 2.9 MoM, and <1.9 MoM, respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11 to 13 weeks, both a nuchal translucency threshold of 1.9 MoM and a fixed threshold of 3.0 mm captured 22 of 93 fetuses (23.7%) with an atypical chromosome abnormality. Of these, 50.0% had a coexisting fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had a better specificity than 3.0 mm. The positive predictive value of an enlarged nuchal translucency for any atypical chromosome abnormality was 1 in 47 for nuchal translucency of >3.0 mm and 1 in 32 for nuchal translucency of >1.9 MoM. Our nuchal translucency threshold of 1.9 MoM captured 0.87% of fetuses, thus approximating the 99th centile. A gestational age-adjusted nuchal translucency threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0 mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged nuchal translucency is more than tripled in the presence of an additional ultrasound abnormality.

Sonologist's characteristics related to a higher quality in fetal nuchal translucency measured in primary antenatal care centers.

To assess the quality of nuchal translucency (NT) measurements in primary care and the sonologist's characteristics related with a higher quality. The median NT expressed in multiples of the median (MoM) was calculated for each sonologist of 14 participating antenatal primary care centers of the Catalan Institute of Health. A survey to the sonologists was used to establish variables related to higher-quality measurements. The median NT MoM obtained in 16 448 NT measurements, performed by 102 sonologists, was 0.94 MoM. NT underestimation was observed in 46% of the sonologists. Underestimation were less frequent among professionals who performed more than 230 ultrasounds per year (26% vs 53%;p=.022), those who completed the online Fetal Medicine Foundation (FMF) course (22% vs 54%; p=.021), and those who were subject to periodic audits (24% vs 56%; p=.021). Underestimation rate decreased from 60%, to 33% and 14% with the increase of the years of experience from less than 5 years, to 6 to 15 years and more than 15 years of experience, respectively (p=.029). Higher-quality measurements were demonstrated in sonologists who performed more ultrasounds per year, those with more years of scanning experience, those who completed the online FMF course, and those periodically audited.

Control de calidad del cribado prenatal de aneuploidías. Control epidemiológico y control de calidad de la medición de la translucencia nucal: resultados de un hospital de tercer nivel durante un periodo de 3 años

Effective screening for Down syndrome can be provided in the first trimester of pregnancy. Quality assurance is an essential aspect of this first-trimester screening. The objective of this study was to evaluate the performance of first-trimester screening in our hospital from April 2010 through April 2013. We obtained an 84.21% detection rate for Down syndrome for a false positive rate of 2.66%. Subsequently, we evaluated the quality of our NT measurements by using the median nuchal translucency multiples of the median (MoM) and found systematic underestimation of NT. Only 30.4% of the sonographers reported median nuchal translucency MoM between 0.9 and 1.1. Our detection rate and false-positive rate were below the standards described by the Fetal Medicine Foundation. The cause was NT underestimation. Nevertheless, we observed a trend toward an improvement in the quality of NT measurements during the 3-year period. Our results are similar to those of other publications. The results of our study show the importance of quality assurance. Training and continual monitoring of data from individual sonographers are needed to ensure that measurements do not deviate.

High macrosomia rate in healthy fetuses after enlarged nuchal translucency

The aim of this study was to investigate the association of the first trimester screening variables nuchal translucency (NT), pregnancy associated plasma protein (PAPP-A), and free beta-human chorionic gonadotrophin (βhCG) and birth weight, with a focus on the prediction of macrosomia. The database of our Fetal Medicine Unit was searched for all singleton pregnancies, who underwent first trimester Down syndrome screening. Live born infants born at term without chromosomal or structural defects from non-diabetic mothers constituted the study population. Birth weight percentiles were corrected for gestational age at delivery, parity, and gender. Macrosomia was defined as birth weight ≥95th centile. We included 6503 fetuses. Multivariate analysis demonstrated that birth weight centile was positively correlated with NT multiples of the median (MoM), PAPP-A MoM, and maternal body mass index, and it was negatively correlated with smoking. An NT ≥95th centile was present in 315 fetuses (4.8%). Although median birth weight centile was not significantly different between cases with NT ≥95th centile and those <95th (P54 vs P52), a birth weight >95th centile was more common (11% vs 7%) in the presence of NT ≥95th centile. Pregnancy associated plasma protein was elevated (≥95th centile) in 303 cases (7.9%). Median birth weight was higher (P56 vs P51, P = 0.03) in case of elevated PAPP-A compared with PAPP-A <95th centile. There was a trend toward higher macrosomia rate in case of PAPP-A ≥95th centile (7.4% vs 6.3%, P = 0.07). Area under the receiver operating characteristics (ROC) curve for the prediction of macrosomia (birth weight ≥95th centile) by NT MoM, PAPP-A MoM, maternal body mass index, and maternal smoking was 0.64 (P < 0.001). First trimester PAPP-A MoM and NT MoM are significantly related to birth weight centiles. Enlarged NT is associated with macrosomia.

596: First trimester screening markers in women with pregestational diabetes mellitus: is a correction factor needed?

595 NIPDT registry–a critical utilization of non-invasive prenatal diagnosis test recently introduced to clinical practice Ossie Geifman-Holtzman, Janet Berman, Amen L Ness, Amy Cohen, Richard Fischer, Amanda Carre, Stuart Weiner Drexel College of Medicine, Obstetrics & Gynecology, Philadelphia, PA, Temple School of Medicine, Obstetrics & Gynecology, Philadelphia, PA, Saint Peters University Hospital, Obstetrics & Gynecology, New Brunswick, NJ, Einstein Medical Center, Genetics & Obstetrics/ Gynecology, Philadelphia, PA, Cooper University Hospital, Obstetrics & Gynecology, Camden, NJ, Thomas Jefferson University Hospital, Obstetrics & Gynecology, Philadelphia, PA OBJECTIVE: To evaluate the accuracy and utilization of noninvasive prenatal diagnosis test (NIPDT) using fetal DNA in maternal blood and to establish a multicenter registry to accomplish this aim. STUDY DESIGN: NIPDT by using fetal DNA in maternal blood to diagnose chromosomal aneuploidy is currently available and its utilization is rapidly expanding. We collected data from 6 centers and tabulated it by patient age, gestational age (GA), indication, maternal serum screen, ultrasound finding. IRB approval was obtained. We have also established the NIPDT Registry to accomplish the above goal. RESULTS: A total of 175 patients underwent testing over the past 3 months. Tests were performed at 11-13 weeks (12%), at 14-17 weeks (36%), at 18-22 (40%) weeks, and at 23-25 (12%) weeks’ gestation. The following indications were used to perform the test: Maternal age (above 35) 54% , Abnormal maternal serum screening 41%, Abnormal ultrasound finding 27% Positive family or personal history 4%. At maternal age of less than 35 about 77%, 15% and 8% were tested because of abnormal ultrasound finding, abnormal serum screen or both abnormal and others, respectively. Inconclusive results were reported to be between 3.5%-5% possible causes: testing at early GA or fetuses with hydrops. Repeat testing at a later GA yielded conclusive results except for one patient. At this time, as most tested patients are undelivered accuracy is determined based on CVS/amniocentesis results with 2% incorrect diagnosis by NIPDT, for example trisomy 18 was reported by NIPDT and was normal by FISH and Karyotype. CONCLUSION: The clinical utilization of NIPDT is rapidly expanding with significant clinical and economical implications. Larger sample size and independent evaluation of the accuracy of all results in clinical setting are clearly required and will be studied by the NIPDT Registry. Current standard of prenatal diagnosis care should continue along with critical assessment of the NIPDT results. 596 First trimester screening markers in women with pregestational diabetes mellitus: is a correction factor needed? Padmalatha Gurram, Peter Benn, Ann-Marie Prabulos, Kisti Fuller, Crawford Christine, Campbell Winston University of Connecticut, Maternal-Fetal Medicine, Farmington, CT, University of Connecticut, Clinical Genetics and developmental biology, Farmington, CT OBJECTIVE: To investigate if maternal serum pregnancy associated plasma protein-A (PAPP-A), total beta hCG and nuchal translucency (NT) measurements differ in women with pregestational diabetes (PGDM) vs. non-diabetic controls (NDC) and if so is a correction factor needed for diabetic women. STUDY DESIGN: We performed a retrospective cohort analysis of all women having a first trimester aneuploidy screen (11 to 13 6 wks) between 1/2005-12/2011 at our facility. The primary outcome was difference in PAPP-A, hCG & NT MoM (multiples of the median, corrected for maternal weight, race, gestational age [GA]) between PGDM and NDC. Women using insulin (IDDM) or oral hypoglycemics (OHG) prior to pregnancy or at the time of screening were classified as PGDM. Known aneuploidy & multifetal gestations were excluded. We also examined if any difference in PAPP-A, hCG and NT between PGDM & NDC is affected by GA or HbA1C.We compared screen positive (1:270)Down syndrome rates (DSR) between PGDM & NDC. Chi square & Mann-Whitney tests were used (significant at p 0.05). RESULTS: Of 6741 eligible patients, 103(1.5%) had IDDM & 4 (0.06%) were on OHG (excluded due to small number). Outcomes were available for 1512 patients, of which 67 (4%) developed gestational diabetes and were excluded. HbA1C was available for 43 IDDM patients. Mean maternal weight in IDDM patients was 202 lbs vs. NDC 161 lbs, (p 0.05). There was a 12% reduction of median PAPP-A & 18 % reduction of median total hCG in women with IDDM (Table). The effect of IDDM on PAPP-A & hCG did not differ with GA (p 0.05).The mean HgbA1C% was 7.3 1.5. There was no significant correlation between HbA1C and PAPP-A (Figure), hCG or NT (p 0.05). Screen positive DSR was 8.74% in IDDM vs. NDC 7.19%, (p 0.03). CONCLUSION: In women with IDDM, PAPP-A and hCG were significantly lower compared to NDC and correction factors should be considered in the aneuploidy calculation of risks for IDDM patients. This effect is not GA dependent or associated with glycemic control. Poster Session IV Academic Issues, Antepartum Fetal, Clinical Ob, Fetus, Genetics, Hypertension, Med-Surg-Diseases, Operative Ob, U/S www.AJOG.org

First trimester risk assessment for trisomy 21 in twin pregnancies combining nuchal translucency and first trimester biochemical markers

The aim is to describe the performance of first-trimester combined risk assessment in twin pregnancies. Maternal serum free beta-human chorionic gonadotrophin and pregnancy-associated plasma protein A (PAPP-A) were determined at 8 to 12 weeks and fetal nuchal translucency (NT) was measured at 11 to 13+6 weeks. The individual risk was estimated for each fetus using the combined test in dichorionic twins. In monochorionic twins, the mean risk assessment of the two fetuses was used. An invasive diagnostic procedure was offered when the risk was ≥ 1 : 270 in either one of the fetuses. From February 2007 to June 2011, 447 twin pregnancies were enrolled in this study. There were 402 (89.9%) dichorionic and 45 (10.1%) monochorionic twins. In dichorionic twins, mean crown-rump length (CRL) was 63.9 mm; median NT multiples of the median (MoM) was 0.97; median Β-hCG was MoM 1.74; median PAPP-A was 1.72. In monochorionic twins, mean CRL was 61.9 mm; median NT MoM was 0. 98; median Β-hCG MoM was 1.44; and median PAPP-A was 1.51. Two pregnancies with Down syndrome were detected by first trimester screening, both in dichorionic twins. The false positive rate was 5.7% (95% confidence interval 4.1-7.3) and 4.4% (95% confidence interval 0.1-8.8%) in dichorionic and monochorionic twins, respectively. The combined test in twins appears to be a good method for Down syndrome screening with a high detection rate and an acceptable false-positive rate.

Impact of nuchal translucency credentialing by the FMF, the NTQR or both on screening distributions and performance

In the USA, both The Fetal Medicine Foundation (FMF) and the Nuchal Translucency Quality Review Program (NTQR) have operated education, review and credentialing for physicians and sonographers for the measurement of nuchal translucency (NT). We sought to assess differences in the distribution of NT measurements based upon the system from which the operator obtained their education, review and credentialing. 398 311 NT measurements by 1541 sonographers who had performed ≥ 50 exams from July 2008 to June 2010 were grouped by organization. Differences between grouped measurements were assessed using analysis of variance of log(10) NT multiples of the median (MoM), with sonographer and organization as factors. MoM values were significantly lower (P ≤ 0.001) and SD was significantly higher (P < 0.001) for the NTQR group compared with the FMF group or those sonographers credentialed by both. The percentage of individuals with negative bias ≥ 10% was greater for the NTQR group (P < 0.001). The difference was less but still significant (P = 0.009) when bias was adjusted for by the overall median for the organization. Although NT MoM measurements were significantly lower and had a wider variance when obtained by the NTQR group, our data cannot distinguish between bias in training or the attributes of the participating sonographers in each program. With these large numbers, it is unlikely that patient characteristics could explain the discrepancy in distributions. Ongoing efforts to monitor sonographer performance with remediation for poor performers may reduce discrepancies between organizations.

The relationship between maternal body mass, smoking status and ethnicity and first trimester nuchal translucency thickness

To investigate the existence of a relationship between maternal body mass, maternal ethnicity and maternal smoking status and nuchal translucency (NT) in the first trimester of pregnancy. NT measurements from 130 339 euploid, singleton pregnancies were converted to NT multiples of the median (MoM) and delta NT using expected medians determined using regression analysis. Relationships between maternal body mass index (BMI), maternal weight, maternal ethnicity and maternal smoking status and NT MoM and delta NT were examined. NT increased with gestational age. Uncorrected NT MoM and delta NT demonstrated small but significant positive relationships with either maternal BMI or maternal weight. Both NT MoM and delta NT were slightly, but significantly, increased in smokers compared to non-smokers and Afro-Caribbean compared to Caucasians, and slightly, but significantly, decreased in Asians compared to Caucasians. Although statistically significant, all the changes reported are likely to be too small to be relevant in terms of correcting in prenatal screening.

Fetal cardiac function between 11 and 35 weeks' gestation and nuchal translucency thickness

The pathophysiological background of an increased nuchal translucency (NT) is still poorly understood. Cardiac dysfunction has been proposed as a cause. The aim of this study was to determine if, in fetuses with normal hearts, the NT thickness is related to cardiac function throughout gestation. The NT was measured in 191 karyotypically/phenotypically normal fetuses with structurally normal hearts and was increased (≥ 95(th) centile) in 104. All fetuses had been referred for fetal echocardiography and were prospectively included between October 1 2003 and April 1 2009. Three-hundred and ten echocardiograms were performed between 11 and 35 weeks' gestation. The E- and A-wave velocity, E/A velocity ratio, E/time velocity integral (TVI) ratio over the atrioventricular (AV) valves, myocardial performance index, acceleration time (AT) and peak velocity over the semilunar valves, stroke volume (SV) and cardiac output (CO) as well as the ductus venosus pulsatility index for veins at 11-14 weeks' gestation (DV-PIV), were measured. A multilevel analysis was performed using the NT multiples of the median (MoM) as a continuous variable. AV-E- and A-wave velocities, E/A velocity ratios, semilunar valve peak velocity, SV, CO and aortic valve (AoV) AT increased significantly with advancing gestation. At 11-14 weeks' gestation, the AoV-AT, tricuspid valve (TV)-E/A, TV-E/TVI ratios and DV-PIV increased, and the pulmonary valve (PV) AT decreased, with increasing NT-MoMs. After midgestation, the PV-AT increased and the AoV-AT, TV-E/A and TV-E/TVI ratios decreased with increasing NT-MoMs. NT thickness is related to right ventricular diastolic function and semilunar valve AT. Our findings suggest improved first-trimester, but later reduced, right ventricular relaxation and discordant ventricular afterload in fetuses with an increased NT.

Ductus venosus pulsatility index measurement reduces the false‐positive rate in first‐trimester screening

To investigate if ductus venosus (DV) pulsatility index for veins (PIV) and a-wave measurements can increase the accuracy of first-trimester Down syndrome screening in a high-risk population. The database of our fetal medicine unit was searched for all cases at increased first-trimester Down syndrome risk. Multivariable logistic regression was used to construct a prediction rule for chromosomal anomalies at any given maternal age, nuchal translucency multiples of the median (NT-MoM) and DV-PIV MoM. The discriminative ability of the model was assessed by using receiver-operating characteristics (ROC) analysis. The study population included 445 fetuses. DV-PIV was increased (≥ 95(th) percentile) in 239 (54%) and DV a-wave was abnormal in 187 fetuses (42%). In this cohort, 80% of all chromosomal anomalies were identified by an increased DV-PIV and 68% by an abnormal a-wave. The odds of chromosomal anomalies increased by a factor of 4.2 per MoM increase in DV-PIV, adjusted for NT and maternal age. The area under the ROC curve for the prediction of chromosomal anomalies was 0.79. After correction for DV-PIV, DV a-wave did not significantly add to the prediction of chromosomal anomalies. In a population of fetuses at increased first-trimester risk for Down syndrome, the combination in a logistic regression model of NT, DV-PIV and maternal age can improve the accuracy of screening for trisomy 21 and other chromosomal anomalies. This is the first study that models the additional value of DV-PIV as a continuous variable to NT measurement alone in a high-risk first-trimester population.

First‐trimester fetal nasal bone length in an ethnic Chinese population

To determine reference ranges of fetal nasal bone length (NBL) in a Chinese population and to assess the value of NBL measurement in screening for chromosomal defects in the first trimester. In this prospective study the fetal profile was examined and the fetal NBL and crown-rump length (CRL) were measured in Chinese women presenting with singleton pregnancies for first-trimester screening for aneuploidy between January 2004 and June 2007. Screening was performed on the basis of nuchal translucency (NT) measurement and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A levels. NBL was measured in 7543 fetuses, of which 7517 were euploid. The best fit equation for median NBL in euploid fetuses in relation to CRL was: NBL (mm) = 0.4593 + (0.0186 x CRL(mm)). The NBL for gestational age (GA, in days) was given by the equation NBL(mm) = 0.2392 + (0.0027 x GA). There was no correlation between log(10)(NBL multiples of the median (MoM)) and log(10)(NT MoM) in unaffected pregnancies (r = - 0.009; P = 0.43). Only two of the 11 cases with trisomy 21 had an NBL outside the 5(th) or 95(th) centiles of the reference range for euploid fetuses. Reference ranges for NBL in a Chinese population suitable for screening for aneuploidy between 11 and 13 + 6 weeks' gestation have been derived. The NBL in Chinese fetuses is similar to that of other ethnic groups. However, unlike the determination of presence vs. absence of the nasal bone, NBL measurement is unlikely to further improve screening for aneuploidy.

Quality assessment of routine nuchal translucency measurements: a North American laboratory perspective

PurposeTo assess nuchal translucency measurements that were performed as part of routine prenatal screening for Down syndrome. MethodsCollect ultrasound measurements of nuchal translucency and crown rump length provided by individual sonographers over a 6-month period to six North American prenatal screening laboratories, along with the laboratory's nuchal translucency interpretation in multiples of the median. For sonographers with 50 or more observations, compute three nuchal translucency quality measures (medians, standard deviations, and slopes), based on epidemiological monitoring. ResultsAltogether, 23,462 nuchal translucency measurements were submitted by 850 sonographers. Among the 140 sonographers (16%) who submitted more than 50 observations, 76 (54%) were found to have all three quality measures in the target range. These 140 sonographers collectively accounted for 14,210 nuchal translucency measurements (61%). The most common single measure to be out of range was nuchal translucency multiples of the median, found for 29 of the 140 sonographers (21%). ConclusionLaboratories should routinely monitor the quality of nuchal translucency measurements that are received for incorporation into Down syndrome screening risk calculations and interpretations. When possible, instituting sonographer-specific medians and providing individualized feedback about performance and numbers of women tested offer the potential to yield more consistent and improved performance.

Maternal serum free‐β‐chorionic gonadotrophin, pregnancy‐associated plasma protein‐A and fetal nuchal translucency thickness at 10–13+6 weeks in relation to co‐variables in pregnant Saudi women

To establish normative values and distribution parameters of first-trimester screening markers, namely, fetal nuchal translucency (NT), maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), at 10 to 13(+6) weeks of gestation in Saudi women and to evaluate the effect of co-variables including maternal body weight, gravidity, parity, fetal gender, twin pregnancy, smoking and ethnicity on these markers. A cohort of Saudi women (first cohort n = 1616) with singleton pregnancies prospectively participated in the present study, and fetal NT together with maternal serum free beta-hCG and PAPP-A were determined at 10 to 13(+6) weeks of gestation. The distribution of gestational age-independent multiples of the median (MoM) of the parameters was defined and normative values were established, and correction for maternal body weight was made accordingly. The influence of various co-variables was examined using the data collected from the first and the second (n = 1849) cohorts of women and 62 twin pregnancies, and compared with other studies. All markers exhibited log-normally distributed MoMs. Gestational age-independent normative values were established. Maternal body weight was corrected, particularly for maternal free beta-hCG and PAPP-A using standard methods. Fetal NT showed a negative relationship with increasing gravidity (r = -0.296) or parity (r = -0.311), whereas both free beta-hCG and PAPP-A exhibited a significant positive relationship. There was a significant increase in the MoM of free beta-hCG in female fetuses. Smoking decreased MoM values of free beta-hCG (by 14.6%; P < 0.01) and PAPP-A (by 18.8%; P < 0.001). Twin pregnancy showed significant increases in MoM values of free beta-hCG (by 1.87-fold) and PAPP-A (by 2.24-fold), with no significant changes in fetal NT MoM values. Fetal NT MoM values were lower in Africans and Asians but higher in Orientals, as compared to Saudi women (P < 0.05; in each case). MoM values (body weight-corrected) of free beta-hCG were 25.2% higher in Africans and 19.4% higher in Orientals but 6.8% lower in other Arabian and Asian (by 5.8%) women as compared to Saudi women (P < 0.05; in each case). The normative values and distribution parameters for fetal NT, maternal serum free beta-hCG and PAPP-A were established in Saudi singleton pregnancies, the maternal body weight together with smoking, twin pregnancy and ethnicity being important first-trimester screening co-variables. Gravidity, parity and fetal gender are also considered to influence one or more of the first-trimester markers examined.

MoM versus Delta NT: Trisomy-21 risk assessment using nuchal translucency (NT) sonography

TRANSLUCENCY (NT) SONOGRAPHY FERGAL D. MALONE, HOWARD CUCKLE, ROBERT H. BALL, DAVID A. NYBERG, CHRISTINE H. COMSTOCK, RADEK BUKOWSKI, KEITH EDDLEMAN, SUSAN J. GROSS, LORRAINE DUGOFF, SABRINA D. CRAIGO, ILAN E. TIMOR, STEPHEN R. CARR, HONOR M. WOLFE, KIMBERLY A. DUKES, MARY E. D’ALTON, Royal College of Surgeons in Ireland, Dublin, Ireland, University of Leeds, Leeds, United Kingdom, University of Utah, Salt Lake City, Utah, Swedish Medical Center, Seattle, Washington, William Beaumont Hospital, Royal Oak, Michigan, University of Texas Medical Branch at Galveston, Galveston, Texas, Mount Sinai School of Medicine, New York, New York, Albert Einstein College of Medicine, Bronx, New York, University of Colorado Health Sciences Center, Denver, Colorado, Tufts University, Boston, Massachusetts, NYU Medical Center, New York, New York, Brown University, Providence, Rhode Island, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, DMSTAT, Boston, Massachusetts, Columbia University, New York, New York OBJECTIVE: To compare the two most commonly used approaches for interpretation of nuchal translucency (NT) sonography for Trisomy-21 risk assessment: multiples of the median (MoM) and Delta NT (NT). STUDY DESIGN: 35,087 patients had NT at 11-13 wks, including 116 cases of Trisomy-21. NT measurements were converted to both MoM and NT. NT MoMs were used with Gaussian likelihood ratios (LRs), and NTs were used with empirical LRs from a large prospective study (Spencer et al, Ultrasound Obstet Gynecol, 2003;22:142), to generate individualized patient risk estimates for Trisomy-21. A 1:270 mid-trimester risk cut-off was used to define screen positivity. RESULTS: NT distribution in unaffected pregnancies was not constant, with inter-tertile ranges of 0.67, 0.75 and 0.83 mm at 11, 12 and 13 wks respectively. The sensitivity of NT with maternal age using NT and empirical LRs was 66% (3.1% FPR), compared with 78% (8.2% FPR) when using NT MoM and Gaussian LRs. At a fixed 5% FPR, detection rates were 71% and 72% respectively. The observed prevalence of Trisomy-21 was closer to that expected from NT MoM-based risks than with the NT approach (see Table). CONCLUSION: Calculating individualized patient risk for Trisomy-21 using NT MoMs is superior to use of NT, with more cases detected, and more accurate risk estimates. (NIH-RO1-HD-38652)

Nuchal translucency in pregnancies conceived after assisted reproduction technology

Levels of maternal serum markers of fetal Down syndrome in pregnancies conceived after assisted reproduction are different from those of normal spontaneous pregnancies. The present study examined the effects of conventional in-vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and embryo cryopreservation on nuchal translucency (NT) thickness. A retrospective analysis on 16 673 spontaneous pregnancies, 119 pregnancies with fresh embryos from IVF, 62 pregnancies with frozen-thawed embryos from IVF, 81 pregnancies with fresh embryos from ICSI and 39 frozen-thawed embryos from ICSI was performed. All were singletons with known normal outcomes. Multiples of the median (MoM) of NT were compared. The median NT MoM of spontaneous pregnancies was 1.01. In the assisted reproduction pregnancies, the median NT MoM were significantly increased to 1.07 (P = 0.003), 1.09 (P = 0.009) and 1.09 (P = 0.001) in pregnancies conceived with fresh embryos from IVF, frozen-thawed embryos from IVF and fresh embryos from ICSI, respectively. A non-significant increase in median NT MoM (1.04; P = 0.489) was also observed in pregnancies with frozen-thawed embryos from ICSI. Increased NT in assisted reproduction pregnancies is postulated to be due to some delay in fetal development. Another possible reason might be related to adverse antenatal course in these pregnancies.

Comparison of pregnancy outcome of euploid fetuses with increased nuchal translucency (NT) expressed in NT MoM or delta-NT.

To evaluate the outcome of euploid fetuses with increased nuchal translucency thickness (NT) expressed in multiples of the median (MoM) or delta-NT. Included in the study were euploid fetuses with increased NT >or= 95(th) centile, for which information about pregnancy outcome was available. The following parameters were defined as an adverse outcome: miscarriage, structural anomalies justifying termination of pregnancy, and structural anomalies, genetic syndromes and neurodevelopmental problems diagnosed postnatally. Fetal outcome according to NT MoM and delta-NT was calculated using different cut-off values. Calculations of the odds ratio for adverse outcome were performed using either NT MoM or delta-NT as a predictor in logistic regression models. The study comprised 168 euploid fetuses. Of these, 38 (23%) had an adverse outcome: 11 (6%) had miscarriages, 14 (8%) were terminated because of fetal abnormalities detected on the prenatal scan and 13 (7%) were found postnatally to have abnormalities. The incidence of cases exhibiting an adverse outcome was 5.3%, 19.2% and 58.5% for NT values of 1.6-1.9, 2.0-3.0 and >3.0 MoM, respectively (P < 0.0001, chi(2) test), and 3.9%, 16.7% and 62.8% for delta-NT values of 1.0-1.4, 1.5-2.5 and >2.5 mm, respectively (P < 0.0001, chi(2) test). Using cut-offs of 2.0 MoM and delta-NT of 1.5 mm, the odds ratios for adverse outcome were 10.2 (95% CI, 3.4-30.4) and 15.4 (95% CI, 4.2-43.6), respectively. Both the NT MoM and delta-NT approaches may be used to determine cases which require additional antenatal investigation as well as fetal karyotyping. For this purpose we suggest using a cut-off of either 2.0 MoM or a delta-NT of 1.5 mm.

Delta-NT or NT MoM: which is the most appropriate method for calculating accurate patient-specific risks for trisomy 21 in the first trimester?

To assess whether in screening for trisomy 21 by nuchal translucency (NT) the delta or the multiples of the median (MoM) approach is the most appropriate method for calculating accurate individual patient-specific risks. Data on fetal NT and crown-rump length from 128,030 unaffected and 428 trisomy 21 pregnancies, measured by sonographers who had obtained The Fetal Medicine Foundation Certificate of Competence in the 11-14-Week Scan, were used. We examined first, if the distribution of NT MoM and log(10)(NT MoM) was Gaussian; second, if the standard deviation of the distributions did not change with gestation; and third, if the median MoM in the affected population was a constant proportion of the median for unaffected pregnancies. All of these features are required to underpin the MoM approach. NT distributions and those of delta-NT were also analyzed. A non-parametric kernel density method was then used to assess the validity of both methods. Errors in the estimation of individual patient-specific risks using the MoM approach were assessed. In the unaffected pregnancies, the distributions of NT MoM and log(10)(NT MoM) were not Gaussian and the standard deviation of log(10)(NT MoM) decreased with gestation. In the trisomy 21 pregnancies, the median NT MoM decreased significantly with gestation, whereas the median delta-NT did not change with gestation. The non-parametric density approach showed that contours of constant likelihood ratio were parallel to the gestational age-dependent median NT values, thus supporting the delta-NT approach. The NT MoM approach resulted in women being given an overestimate of risk for trisomy at 11 weeks and a considerable underestimate of risk at 13 weeks. In the calculation of risk for trisomy 21 by NT the NT MoM approach is inaccurate and inappropriate because the underlying assumptions are not valid. In contrast, the delta-NT approach gives accurate estimates of risks.

The effect of ethnic origin on nuchal translucency at 10-14 weeks of gestation.

Fetal nuchal translucency (NT) increases with gestation and is affected by fetal posture and fetal gender. A recent report suggested that there might also be ethnic differences. We investigated the effect of ethnic origin on NT in an Asian population. NT was measured at 10-14 weeks. The measurements were converted into multiples of the median (MoM) for gestational day. The risk of Down syndrome was calculated by combining NT and maternal age. Cases affected by chromosomal and major structural abnormalities were excluded. NT measurements of different ethnic groups were compared. Between January 1997 and October 2001, 16 981 pregnancies with known ethnic origin and normal fetal outcome were analysed. Median NT MoM (95% CI) of the Filipinos was 1.07 (1.04-1.11). This was significantly higher than that of the Chinese, 1.01 (1.01-1.02); other Asians (Indians, Pakistanis and Nepalese), 0.96 (0.94-0.99), and Caucasians, 0.98 (0.93-1.06) (p<0.05, respectively; Mann-Whitney U-test). An NT risk cut-off of 1:180 would classify 5% of the Chinese, 4.6% of the Caucasians, 5.6% of the Filipinos and 4.2% of the other Asians as screen-positive. There were no statistically significant differences between these screen-positive rates (p>0.05, Chi-square test). Although there were statistically significant differences in NT measurements between different ethnic groups, it was clinically insignificant, as reflected by similar screen-positive rates.

Quality assessment in prospective nuchal translucency screening for Down syndrome.

To develop and apply a quality control system in a Down syndrome screening study using nuchal translucency as an interventional marker. In a prospective Down syndrome screening study fetal nuchal translucency thickness was measured in 9236 of the 10 045 examined pregnancies. For quality assessment two models were introduced: firstly, image-scoring evaluation of the nuchal translucency thickness measurements and secondly, establishment of the distributions of nuchal translucency multiples of the median over time and the influence of intervention. The observer variability in the image-scoring evaluation was high with a kappa value of 0.48 in the overall validation. A revised model showed better interobserver agreement with a kappa value of 0.58; however, comparing the individual criteria the differences were still unsatisfactory, i.e. we found highly significant differences in the criteria "position of the fetus" (P = 0.0026) and "magnification of the image" (P = 0.0001). Regarding the distributions of the nuchal translucency multiples of the median, the median stabilized after a short learning phase representing the practical part of the sonographer's certification to nuchal translucency screening. In groups of medians of 50 nuchal translucency multiples of the median the intergroup standard deviation decreased from 0.100-0.060 after the learning phase to 0.046 after intervention. When well-trained certified examiners perform nuchal translucency screening, continuous evaluation of the distribution of the nuchal translucency multiples of the median seems to be a good method to assess the quality for a center and may also be used to identify individual examiners deviating from the mean performance. The image-scoring methods we introduced cannot be recommended for quality control in a nuchal translucency screening program.