Ultrasound in Obstetrics and Gynecology

Objectives To assess the detection rate of triploidy at first-trimester screening for trisomy 21 and evaluate outcome in triploid pregnancies. Methods From 2008 to 2011, 198427 women with singleton pregnancies underwent first-trimester screening between 11+2 and 14+0weeks' gestation. Screening parameters included nuchal translucency, maternal serum free -human chorionic gonadotropin (-hCG) and pregnancy-associated plasma protein-A (PAPP-A). In all triploid fetuses, these parameters were re-evaluated. Karyotypes were established by invasive testing (chorionic villus sampling or amniocentesis) or postabortem and obtained from the Danish Cytogenetic Central Register and the Danish Fetal Medicine Database. ResultsA total of 30 triploid fetuses underwent first-trimester screening. Twenty-five were diagnosed as a result of abnormal first-trimester scan findings, a detection rate of 83.3%. Twenty-three fetuses were identified due to a high risk for trisomy 13, 18 or 21 and two fetuses due to structural abnormalities. The incidence of triploidy at first-trimester screening was 1:6614. A smaller crown-rump length than that estimated by date of last menstrual period was found in 95% of the fetuses with data available for evaluation. Eight fetuses had a larger biparietal diameter than expected for gestational age. Fetuses with a 69,XXX karyotype had significantly lower multiples of the median values for -hCG and PAPP-A than did 69,XXY fetuses (P=0.045 and P=0.02 for-hCG and PAPP-A, respectively). No infants with triploidy were born in the study period. Among the triploid gestations detected on first-trimester screening, 20 (80.0%) women chose termination of pregnancy, four (16.0%) had spontaneous miscarriage and one (4.0%) was stillborn. Conclusion First-trimester screening for trisomy 21 also provides a high detection rate for triploidy. Copyright (c) 2013 ISUOG. Published by John Wiley & Sons Ltd.

To confirm the results from two previous evaluations of term prediction models, including two sample-based models and one population-based model, in a third population. In a study population of 23,020 second-trimester ultrasound examinations, data were prospectively collected and registered over the period 1988-2009. Three different models for ultrasonically estimated date of delivery were applied to the measurements of fetal biparietal diameter (BPD) and two models were applied to the femur length (FL) measurements; the resulting term estimations were compared with the actual time of delivery. The difference between the actual and the predicted dates of delivery (the median bias) was calculated for each of the models, for three BPD/FL-measurement subgroups and for the study population as a whole. For the population-based model, the median bias was + 0.4 days for the BPD-based predictions and - 0.4 days for the FL-based predictions, and the biases were stable over the inclusion ranges. The biases of the two traditional models varied with the size of the fetus at examination; median biases were - 0.87 and + 2.2 days, respectively, with extremes - 4.2 and + 4.8 days for the BPD-based predictions, and the median bias was + 1.72 days with range - 0.8 to + 4.5 days for FL-based predictions. The disagreement between the two sample-based models was never less than 2 days for the BPD-based predictions. This study confirms the results from previous studies; median biases were negligible with term predictions from the population-based model, while those from the traditional models varied substantially. The biases, which have clinical implications, seem inevitable with the sample-based models, which, even if overall biases were removed, will perform unsatisfactorily.

To evaluate the performance of a one-stop clinic for assessment of risk (OSCAR) for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free β-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11–14 weeks of gestation. Screening for trisomy 21 was carried out by OSCAR in 15 030 singleton pregnancies with live fetuses at 11–14 weeks. The estimated risk for trisomy 21 was calculated, and the women were counseled regarding this risk and the option of invasive testing or expectant management. Follow-up of the outcome of all pregnancies was carried out. The detection and false-positive rates for different risk cut-offs were calculated. Fetal NT and maternal serum free β-hCG and PAPP-A were successfully measured in all cases. Pregnancy outcome, including karyotype results or the birth of a phenotypically normal baby, was obtained from 14 383 cases. The median maternal age of these cases was 34 (range 15–49) years and in 6768 (47.1%) the age was 35 years or greater. The median gestation at screening was 12 (range 11–14) weeks and the median fetal crown–rump length was 64 (range 45–84) mm. The estimated risk for trisomy 21 based on maternal age, fetal NT and maternal serum free β-hCG and PAPP-A was 1 in 300 or greater in 6.8% (967 of 14 240) normal pregnancies, in 91.5% (75 of 82) of those with trisomy 21 and in 88.5% (54 of 61) of those with other chromosomal defects. For a fixed false-positive rate of 5% the respective detection rates of screening for trisomy 21 by maternal age alone, maternal age and serum free β-hCG and PAPP-A, maternal age and fetal NT, and by maternal age, fetal NT and maternal serum biochemistry were 30.5%, 59.8%, 79.3% and 90.2%, respectively. Screening for trisomy 21 by a combination of maternal age, fetal NT and maternal serum biochemistry at 11–14 weeks can be provided in an OSCAR setting and is associated with a detection rate of about 90% for a false-positive rate of 5%. Copyright © 2002 International Society of Ultrasound in Obstetrics and Gynecology

Objectives: Monochorionic (MC) twins are at increased risk of early fetal loss secondary to vascular complications such as twin-twin transfusion syndrome (TTTS). The aim of this study is to compare the early perinatal loss rates between MC and dichorionic (DC) twins in an era of invasive treatment for TTTS. Methods: This was a retrospective study of all twin pregnancies of known chorionicity from a large regional cohort of 9 hospitals over a ten year period. Ultrasound data were matched to hospital delivery records and a mandatory national register of pregnancy losses. Prospective risk of pregnancy loss from 14 to 24 weeks' gestation was calculated and the survival trend of MC and DC twins was analysed using Kaplan-Meier survival analysis. Results: The analysis included 3117 twin pregnancies (605 MC and 2512 DC). The total risk of early pregnancy loss (miscarriage and neonatal death) before 24 weeks in MC twins (60.3 per 1000 fetuses) was significantly higher than in DC twins (6.5 per 1000 fetuses), with a hazard ratio (HR) of 9.18 (95% CI, 6.0-13.9). Survival analysis showed a significant difference in overall and early mortality between MC and DC twins (Log-rank test, p<0.0001), while no difference was noted after 24 weeks of gestation (Log-rank test, p=0.08). Conclusions: Early pregnancy loss is significantly more common in MC than in DC twins, but the trend in prospective risk of mortality in MC twins is not evident after 24 weeks' gestation. This rate has almost halved compared to those in the published literature. Early detection and prompt treatment of complications in MC twins is likely to have contributed to this improvement in outcomes. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

To examine the accuracy of sonographic findings of routine ultrasound examinations in patients with a proven histological diagnosis of complete or partial hydatidiform mole referred to a supra-regional referral center, and to examine the relationship of sonographic findings to gestational age across the first and early second trimesters. Review of consecutive cases referred to a trophoblastic disease unit from June 2002 to January 2005 with a diagnosis of possible or probable hydatidiform mole in whom results of a pre-evacuation ultrasound examination were documented. Ultrasound detection rates for partial and complete hydatidiform moles were calculated and comparison of detection rates between complete and partial mole, and gestational age groups carried out. 1053 consecutive cases were examined. The median maternal age was 31 (range, 15-54) years and the median gestational age was 10 (range, 5-27) weeks. 859 had a final review diagnosis of partial or complete hydatidiform mole (82%), including 253 (29%) complete moles and 606 (71%) partial moles. Non-molar hydropic miscarriage was diagnosed following histological review in 194 (18%). Overall, 378 (44%) cases with a final diagnosis of complete or partial hydatidiform mole had a pre-evacuation ultrasound diagnosis suggesting hydatidiform mole, including 200 complete moles and 178 partial moles, representing 79% and 29%, respectively, of those with complete (253) or partial (606) moles in the final review diagnosis. The ultrasound detection rate was significantly better for complete versus partial hydatidiform moles (Z = 13.4, P < 0.001). There was a non-significant trend towards improved ultrasound detection rate with increasing gestational age, with an overall detection rate of 35-40% before 14 weeks' gestation compared to around 60% after this gestation. The sensitivity, specificity, positive predictive value and negative predictive value for routine pre-evacuation ultrasound examination for detection of hydatidiform mole of any type were 44%, 74%, 88% and 23%, respectively. Routine pre-evacuation ultrasound examination identifies less than 50% of hydatidiform moles, the majority sonographically appearing as missed or incomplete miscarriage. Detection rates are, however, higher for complete compared to partial moles, and improve after 14 weeks' gestation. Histopathological examination of products of conception remains the current gold standard for the identification of gestational trophoblastic neoplasia.

In 1015 fetuses undergoing first-trimester karyotyping because of increased nuchal translucency thickness, the incidence of chromosomal abnormalities increased with both maternal age and nuchal translucency thickness. The observed numbers of trisomies 21, 18 and 13 in fetuses with nuchal translucency thicknesses of 3 mm, 4 mm, 5 mm and > or = 6 mm were approximately 3 times, 18 times, 28 times and 36 times higher than the respective numbers expected on the basis of maternal age. The incidences of Turner syndrome and triploidy were 9-fold and 8-fold higher but the incidence of other sex chromosome aneuploidies was similar to that of an unselected population of women undergoing first-trimester fetal karyotyping for maternal age. In the chromosomally normal group, the incidence of structural defects, mainly cardiac, diaphragmatic, renal and abdominal wall, was approximately 4%, which is higher than would be expected in an unselected population. The rates of fetal loss in the groups with nuchal translucency thickness of 3 mm and 4 mm were 2% and 4%, respectively, which is similar to the 2.3% rate of fetal loss observed in a group of fetuses with normal nuchal translucency thickness undergoing chorion villus sampling. For fetal nuchal translucency thickness of > or = 5 mm, the rate of fetal loss was 13%.

To evaluate whether real-time elastography, a new, non-invasive method for the diagnosis of breast cancer, improves the differentiation and characterization of benign and malignant breast lesions. Real-time elastography was carried out in 108 potential breast tumor patients with cytologically or histologically confirmed focal breast lesions (59 benign, 49 malignant; median age, 53.9 years; range, 16-84 years). Tumor and healthy tissue were differentiated by measurement of elasticity based on the correlation between tissue properties and elasticity modulus. Evaluation was performed using the three-dimensional (3D) finite element method, in which the information is color-coded and superimposed on the B-mode ultrasound image. A second observer evaluated the elastography images, in order to improve the objectivity of the method. The results of B-mode scan and elastography were compared with those of histology and previous sonographic findings. Sensitivities and specificities were calculated, taking histology as the gold standard. B-mode ultrasound had a sensitivity of 91.8% and a specificity of 78%, compared with sensitivities of 77.6% and 79.6% and specificities of 91.5% and 84.7%, respectively, for the two observers evaluating elastography. Agreement between B-mode ultrasound and elastography was good, yielding a weighted kappa of 0.67. Our initial clinical results suggest that real-time elastography improves the specificity of breast lesion diagnosis and is a promising new approach for the diagnosis of breast cancer. Elastography provides additional information for differentiating malignant BI-RADS (breast imaging reporting and data system) category IV lesions.

Methods: This 4 1 2 year retrospective study is based on 71 fetuses where termination of pregnancy (TOP) was performed because of a fetal malformation and/or chromosomal anomaly. Only fetuses who had undergone both fetal anatomy scanning and autopsy were included. Sensitivity and specificity of ultrasound findings with regard to autopsy findings were calculated. In addition, the fetuses were grouped into four categories depending on the degree of concordance between ultrasound and autopsy. Results: The sensitivity of ultrasound was highest for malformations in the cerebro-spinal and internal organ systems (100% and 91%), while many of the malformations in the cardiovascular and skeletal organ systems were detected only at autopsy (sensitivity of ultrasound 63% and 71%, respectively). The specificity of ultrasound was lowest for the internal and cerebro-spinal organ systems (87% and 89%). There was complete agreement between ultrasound and autopsy findings in 44% of the fetuses and a 'near match' in 46%. In 10% of the fetuses, the ultrasound findings were only partially confirmed or not confirmed at all by autopsy. The false positive ultrasound diagnoses were not crucial for the parents decision to terminate the pregnancy. Conclusions: Despite overall good agreement between ultrasound and autopsy findings, the ultrasound examinations were suboptimal for some organ systems. The detection rate was lowest for cardiovascular anomalies. Autopsy often provided important additional information unobserved at ultrasound examination.

To examine the pattern of growth in chromosomally abnormal fetuses at 11+0 to 13+6 weeks of gestation and compare the trunk and head volume to crown-rump length (CRL) in defining the growth deficit in such fetuses. The fetal trunk and head volume was measured using three-dimensional (3D) ultrasound in 140 chromosomally abnormal fetuses at 11+0 to 13+6 (median 12) weeks of gestation, and the values were compared to 500 chromosomally normal fetuses. In each chromosomally abnormal fetus, the observed fetal trunk and head volume was subtracted from the expected mean (delta value) of the chromosomally normal fetuses of the same gestational age, and this difference was expressed as a percentage of the appropriate normal mean. The Mann-Whitney U-test was used to determine the significance of differences between the chromosomally normal and abnormal groups. In trisomy 21 (n=72) and Turner syndrome (n=14) fetuses, compared to chromosomally normal fetuses, the CRL for gestation was similar (P=0.335 and P=0.317, respectively), but the fetal trunk and head volume was about 10-15% lower (P<0.001 and P=0.004, respectively). In trisomy 18 (n=29), trisomy 13 (n=14) and triploidy (n=11), the deficit in volume was about 45% (P<0.001), whereas the deficit in CRL was less than 15% (P<0.001). In the quantification of the degree of early growth impairment in chromosomally abnormal fetuses, measurement of the fetal trunk and head volume using 3D ultrasound may be better than measurement of CRL.

To determine the pattern of early growth disturbance in chromosomally abnormal fetuses by comparing the volume of the fetal head to that of the trunk. The fetal trunk and head volume was measured using three-dimensional (3D) ultrasound in 145 chromosomally abnormal fetuses at a median gestational age of 12 (range, 11 + 0 to 13 + 6) weeks. The head volume was measured separately and then subtracted from the total head and trunk volume to obtain the volume of the fetal trunk. The head-to-trunk ratios were then calculated and the Mann-Whitney U-test was used to determine the significance of differences from 500 chromosomally normal fetuses. The fetal head volume for crown-rump length (CRL) was significantly smaller than normal in trisomy 21, trisomy 13 and Turner syndrome (P < 0.001, P < 0.001 and P = 0.001, respectively), whereas no significant differences were found in trisomy 18 and triploidy (P = 0.139 and P = 0.070, respectively). The fetal trunk volume for CRL was significantly smaller in all chromosomal abnormalities (P < 0.001) except Turner syndrome (P = 0.134). The head-to-trunk ratio for CRL was significantly larger in trisomy 18, trisomy 13 and triploidy (P < 0.001), but normal in trisomy 21 (P = 0.221) and Turner syndrome (P = 0.768). In trisomy 21 and Turner syndrome, the growth deficit was symmetrical with the head and trunk being equally affected, whereas in triploidy and trisomies 18 and 13 there was asymmetrical growth restriction with the trunk being more severely compromised than the head.

Objective To ascertain the reported association between reduced biparietal diameter (BPD) at 11-13 weeks' gestation and open spina bifida and to investigate its predictive value in a single-center study. Methods This was a retrospective study of fetuses in which BPD was measured at 11-13 weeks' gestation, including 27 fetuses with isolated open spina bifida subsequently diagnosed at 16-24 weeks and 7775 unaffected controls. BPD values were converted into multiples of the expected median (MoM) after adjustment for crown-rump length and maternal characteristics. Multivariable logistic regression analysis was used to determine the maternal characteristics significantly associated with spina bifida. The performance of screening was determined by receiver-operating characteristics curve analysis. BPD values at 11-13 weeks' gestation were compared with those measured in the second trimester using Z-scores. ResultsBPD values at 11-13 weeks' gestation were below the 5(th) centile in 44.4% of cases of open spina bifida. In these fetuses, the median BPD MoM value was significantly smaller than that in the control group (0.930 vs 0.998 MoM; P < 0.0001). Multivariable logistic regression analysis showed a significant contribution from maternal age (P = 0.008) and BMI (P = 0.028) to the association between BPD MoM and spina bifida. The detection rate using BPD measurements in the first trimester was 55.6% with a false-positive rate of 11.6%. In fetuses with open spina bifida, the BPDZ-scores were significantly lower at 16-24 weeks compared to those recorded at 11-13 weeks (median, -1.71 (range, -3.98 to -0.20) vs -1.30 (-3.75 to 2.61); P = 0.006). Conclusion Fetuses with open spina bifida have a smaller BPD in the first trimester. This observation may be useful in early screening. It is likely that a combination of maternal characteristics such as age and BMI, fetal BPD and maternal serum alpha-fetoprotein measured in the first trimester would provide a clinically useful screening test for open spina bifida. Copyright (c) 2013 ISUOG. Published by John Wiley & Sons Ltd.

To describe the sonographic appearance of the structures of the posterior cranial fossa in fetuses at 11 + 3 to 13 + 6 weeks of pregnancy and to determine whether abnormal findings of the brain and spine can be detected by sonography at this time. This was a prospective study including 692 fetuses whose mothers attended Innsbruck Medical University Hospital for first-trimester sonography. In 3% (n = 21) of cases, measurement was prevented by fetal position. Of the remaining 671 cases, in 604 there was either a normal anomaly scan at 20 weeks or delivery of a healthy child and in these cases the transcerebellar diameter (TCD) and the anteroposterior diameter of the cisterna magna (CM), measured at 11 + 3 to 13 + 6 weeks, were analyzed. In 502 fetuses, the anteroposterior diameter of the fourth ventricle (4V) was also measured. In 25 fetuses, intra- and interobserver repeatability was calculated. We observed a linear correlation between crown-rump length (CRL) and CM (CM = 0.0536 × CRL - 1.4701; R2 = 0.688), TCD (TCD = 0.1482 × CRL - 1.2083; R2 = 0.701) and 4V (4V = 0.0181 × CRL + 0.9186; R2 = 0.118). In three patients with posterior fossa cysts, measurements significantly exceeded the reference values. One fetus with spina bifida had an obliterated CM and the posterior border of the 4V could not be visualized. Transabdominal sonographic assessment of the posterior fossa is feasible in the first trimester. Measurements of the 4V, the CM and the TCD performed at this time are reliable. The established reference values assist in detecting fetal anomalies. However, findings must be interpreted carefully, as some supposed malformations might be merely delayed development of brain structures.

To assess whether extremes in nuchal translucency (NT) thickness measurements at 11-14 weeks of gestation are preceded by departures from normal in early ultrasound biometry or embryonic heart rate in euploid fetuses. This was a retrospective analysis of data from women with singleton pregnancies examined in early pregnancy between June 2002 and January 2003, who subsequently had a nuchal translucency (NT) scan. The early pregnancy scan was performed transvaginally, and the crown-rump length (CRL), mean gestational sac diameter (GS), mean yolk sac diameter (YS) and embryonic heart rate (HR) were measured where possible. At the second scan CRL and NT were measured. A total of 534 singleton pregnancies were included in the analysis. The mean maternal age was 30 (range, 14-45) years, and 59.4% of the patients were nulliparous. The mean CRL was 11.5 (range, 1.4-30.0) mm at the first scan and 62.8 (range, 42.0-88.0) mm at the second scan. GS, YS and HR measurements were obtained in 87.6%, 72.5% and 72.5% of cases, respectively. No statistically significant correlation was observed between NT and Z-scores of early pregnancy: GS (r = 0.013, P = 0.77), YS (r = 0.039, P = 0.44) or HR (r = 0.016, P = 0.76). GS, YS and HR were not significantly different in fetuses with NT measurements below the 10th percentile or above the 90th percentile (P = 0.24, 0.84 and 0.60, respectively). Ultrasound biometry and heart rate measured in early pregnancy are not related to nuchal translucency measurements at 11-14 weeks of gestation in chromosomally normal fetuses.

To construct gestational age (GA)-based reference ranges for the uterine artery (UtA) mean pulsatility index (PI) at 11-41 weeks of pregnancy. A prospective cross-sectional observational study was carried out of 20 consecutive singleton pregnancies for each completed gestational week at 11-41 weeks. UtAs were examined by color and pulsed Doppler imaging, and the mean PI, as well as the presence or absence of a bilateral protodiastolic notch, were recorded. Polynomials were fitted by means of least-square regression to estimate the relationship between the mean UtA-PI and GA. A total of 620 women were included. A second-degree polynomial (Log(e) mean UtA-PI = 1.39 - 0.012 x GA + GA(2) x 0.0000198, with GA measured in days), after a natural logarithmic transformation, was selected to model our data. There was a significant decrease in the mean UtA-PI between 11 weeks (mean PI, 1.79; 95(th) centile, 2.70) and 34 weeks (mean PI, 0.70; 95(th) centile, 0.99). It then became more stable up until 41 weeks (mean PI, 0.65; 95(th) centile, 0.89). The mean UtA-PI shows a progressive decrease until the late stages of pregnancy. Reference ranges for mean UtA-PI may have clinical value in screening for placenta-associated diseases in the early stages of pregnancy, and in evaluating patients with pregnancy-induced hypertension and/or small-for-gestational age fetuses during the third trimester.

A discrepancy in crown-rump length (CRL) and/or nuchal translucency thickness (NT) between monochorionic twins has been found to be associated with an increased risk of twin-twin transfusion syndrome (TTTS). As one of the most plausible mechanisms for increased NT is hemodynamic imbalance and cardiac dysfunction, indirectly manifested by abnormal blood flow in the ductus venosus (DV), we aimed to clarify the role of DV blood flow assessment in identifying those monochorionic twins more prone to develop TTTS. We present 99 cases of monochorionic diamniotic twin pregnancies in which CRL, NT and DV blood flow were evaluated at 11-14 weeks' gestation. Discrepant values of CRL were not predictive of TTTS development. Intertwin NT discrepancy >or= 0.6 mm had a sensitivity of 50.0% and a specificity of 92.0%. The presence of at least one abnormal blood flow waveform in the DV was associated with a relative risk for developing TTTS of 11.86 (95% CI, 3.05-57.45), with a sensitivity of 75.0% and a specificity of 92.0%. The combination of abnormal DV blood flow with NT discrepancy >or= 0.6 mm yielded a relative risk for the development of TTTS of 21 (95% CI, 5.47-98.33). Both intertwin discrepancy in NT and abnormal flow in the DV in monochorionic twins may represent early manifestations of hemodynamic imbalance between donor and recipient. In these pregnancies, in addition to NT measurement at 11-14 weeks, the Doppler assessment of DV blood flow significantly increases the performance of screening for those at risk of developing TTTS.

To assess the influence of the presence of nuchal cord (NC) on the evaluation of the fetal ductus venosus flow velocity waveform (DV-FVW). This prospective study included 1174 normal non-selected singleton pregnancies between 11 and 13 + 6 weeks' gestation. We recorded the presence or absence of NC around the fetal neck, and assessed its relationship with the qualitative assessment and quantitative measurement of the DV-FVW. We observed NC around the fetal neck in 6.73% of cases and detected reversed flow of the a-wave of the DV-FVW in 2.98% of cases. In the group without NC, 21 of 1095 had reversed flow in the DV-FVW (1.9%; 95% CI, 1.28-3.02), whereas in the group with NC, 14 of 79 had reversed flow in the DV-FVW (17.7%; 95% CI, 16.67-40.35). We found a lower pulsatility index in fetuses without NC in comparison to those with NC (P < 0.001). We also found an association between the presence of NC and an increased occurrence of absent and reversed a-wave of the flow velocity waveforms (P < 0.001). On multivariate logistic regression analysis, a much higher occurrence of reversed DV-FVW a-wave was detected in fetuses with NC and smaller crown-rump length, and a much higher occurrence of absent DV-FVW a-wave was found in fetuses with NC and a higher maternal body mass index. The presence of NC modifies the sonographic findings in the qualitative and quantitative evaluation of the DV-FVW.

To examine the possible effects of maternal and fetal characteristics on the fetal fraction in maternal plasma cell-free (cf) DNA at 11–13 weeks' gestation and estimate the proportion of pregnancies at high risk of non-invasive prenatal testing (NIPT) failure because the fetal fraction is less than 4%. In 1949 singleton pregnancies at 11–13 weeks' gestation cf-DNA was extracted from maternal plasma. Chromosome-selective sequencing of non-polymorphic and polymorphic loci, where fetal alleles differ from maternal alleles, was used to determine the proportion of cf-DNA that was of fetal origin. Multivariable regression analysis was used to determine significant predictors of the fetal fraction among maternal and fetal characteristics. The fetal fraction decreased with increased maternal weight, it was lower in women of Afro-Caribbean origin than in Caucasians and increased with fetal crown–rump length, serum pregnancy-associated plasma protein-A, serum free β-human chorionic gonadotropin, smoking and trisomy 21 karyotype. The median fetal fraction was 10.0% (interquartile range, 7.8–13.0%) and this decreased with maternal weight from 11.7% at 60 kg to 3.9% at 160 kg. The estimated proportion with fetal fraction below 4% increased with maternal weight from 0.7% at 60 kg to 7.1% at 100 kg and 51.1% at 160 kg. Fetal fraction in maternal plasma cf-DNA is affected by maternal and fetal characteristics.Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.

To examine the relationship between the measurement of nuchal translucency in the first trimester and nuchal fold in the second trimester in normal pregnancy. This was a prospective study of 592 singleton pregnancies. Fetal nuchal translucency was measured at 11-14 weeks of gestation and nuchal fold at 20-24 weeks of gestation. Linear regression models were used to assess the relationship between nuchal translucency and nuchal fold after adjustment for gestational age. There was no significant association between nuchal translucency and nuchal fold thickness. It is possible that measurement of nuchal translucency and nuchal fold may provide an independent contribution in screening for trisomy 21.

To determine the number of ultrasound examinations necessary for training sonographers to examine accurately the fetal nasal bone at 11-14 weeks' gestation. Fifteen sonographers with experience in measuring nuchal translucency were asked to examine the nasal bone during the routine 11-14-week scan. The supervising doctor recorded if the sonographer succeeded in obtaining the correct image. Each sonographer performed a total of 140 examinations, and the data were analyzed in seven groups of 20 examinations. In a second study, two sonographers with extensive experience in examining the nasal bone examined independently 100 consecutive patients at a median fetal crown-rump length of 65 (45-84) mm and median gestational age of 12 (11-14) weeks and recorded whether the nasal bone was absent or present. In the first group of 20 examinations, there was failure to obtain the correct image of the fetal profile in 1-5 (median, 4) cases. In the subsequent three groups, there was failure to obtain the correct image in 0-3 (median, 1) cases. In the fifth and sixth groups failure occurred in 0-2 (median, 0) cases and in the seventh group all sonographers obtained successful images of the fetal profile in all cases. One sonographer obtained successful images of all cases after the first 40 scans, four after the first 60 scans, six after the first 80 and two each after the first 100 and 120 scans. In the second study, there was agreement between the two sonographers that the nasal bone was absent in two and present in 98 of the 100 consecutive patients examined. The minimum number of scans required for an experienced sonographer to become competent in examining the fetal nasal bone is on average 80, with a range of 40-120.

To assess the fetal loss rate following amniocentesis and chorionic villus sampling (CVS). This was a national registry-based cohort study, including all singleton pregnant women who had an amniocentesis (n = 32 852) or CVS (n = 31 355) in Denmark between 1996 and 2006. Personal registration numbers of women having had an amniocentesis or a CVS were retrieved from the Danish Central Cytogenetic Registry, and cross-linked with the National Registry of Patients to determine the outcome of each pregnancy. Postprocedural fetal loss rate was defined as miscarriage or intrauterine demise before 24 weeks of gestation. The miscarriage rates were 1.4% (95% CI, 1.3-1.5) after amniocentesis and 1.9% (95% CI, 1.7-2.0) after CVS. The postprocedural loss rate for both procedures did not change during the 11-year study period, and was not correlated with maternal age. The number of procedures a department performed had a significant effect on the risk of miscarriage. In departments performing fewer than 500 amniocenteses, the odds ratio for fetal loss was 2.2 (95% CI, 1.6-3.1) when compared to departments performing more than 1500 procedures during the 11-year period. For CVS the risk of miscarriage was 40% greater in departments performing 500-1000 and 1001-1500 as compared to those performing more than 1500 procedures. The miscarriage rates (i.e. spontaneous loss and procedure-related loss) after amniocentesis and CVS were 1.4% and 1.9%, respectively. This difference may be explained by the difference in gestational age at the time of the procedures. The miscarriage rate was inversely correlated with the number of procedures performed in a department.

To evaluate the performance of screening for pre-eclampsia by uterine artery pulsatility index (PI) at 11 + 0 to 13 + 6 weeks' gestation and the change in uterine artery PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks. In 3107 singleton pregnancies attending for routine care at 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks' gestation we recorded maternal characteristics and medical and obstetric history, and measured uterine artery PI. The distributions of uterine artery PI were made Gaussian after logarithmic transformation and the log of the ratio of uterine artery PI at 21 + 0 to 24 + 6 weeks to that at 11 + 0 to 13 + 6 weeks was calculated. Multiple regression analysis was used to determine which of the maternal variables and Doppler findings were significant predictors of early and late pre-eclampsia. The performance of screening was described by receiver-operating characteristics curves. Pre-eclampsia developed in 93 (3.0%) pregnancies, including 22 (0.7%) in which delivery was before 34 weeks (early pre-eclampsia) and 71 (2.3%) with delivery at 34 weeks or more (late pre-eclampsia). Seventy-three (2.3%) women developed gestational hypertension, 346 (11.1%) delivered small-for-gestational-age (SGA) babies with no hypertensive disorders and 2595 (83.5%) were unaffected by pre-eclampsia, gestational hypertension or SGA. Multiple regression analysis demonstrated that maternal variables, uterine artery PI at 11 + 0 to 13 + 6 weeks and the change in uterine artery PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks' gestation provided significant independent contributions to the prediction of pre-eclampsia. For a false positive rate of 5% the predicted detection rates of early and late pre-eclampsia were 90.9 and 31.0%, respectively. The same performance of screening was achieved by reserving second-trimester testing for only the 20% of women at the highest risk after first-trimester screening. The decrease in uterine artery PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks is steeper in pregnancies with a normal outcome than in those developing pre-eclampsia. Effective screening for pre-eclampsia can be achieved by the Doppler measurement of uterine artery PI at 11 + 0 to 13 + 6 weeks and the change in PI between 11 + 0 to 13 + 6 and 21 + 0 to 24 + 6 weeks.

To examine the possible association between aneuploidies and fetal lateral cerebral ventriculomegaly in the first trimester of pregnancy. Three-dimensional brain volumes were acquired by transvaginal ultrasound examination at 11-13 weeks' gestation in 410 euploid fetuses and 63 fetuses with trisomy 21, 34 with trisomy 18 and seven with trisomy 13. Lateral ventricles were assessed in a transverse view, just above the roof of the third ventricle and measurements of the areas of the lateral ventricles and choroid plexuses were obtained. The ratio between choroid plexus and lateral ventricle areas (CLR) was calculated. Measurements in aneuploid fetuses were compared to those in euploid fetuses. In euploid fetuses the lateral ventricle and choroid plexus areas increased, whereas the CLR decreased with fetal biparietal diameter. In fetuses with trisomy 21, lateral ventricle and choroid plexus areas were smaller but CLR was not significantly different from that in euploid fetuses. In trisomy 18 and 13 fetuses, CLR was significantly smaller than in euploid fetuses. The CLR was below the 5(th) centile of normal range in 11 (32.4%) fetuses with trisomy 18 and in six (85.7%) with trisomy 13. There is evidence of ventriculomegaly at 11-13 weeks' gestation in most fetuses with trisomy 13 and one third of fetuses with trisomy 18.

Fetal hydranencephaly is a rare congenital cerebral abnormality characterized by complete or near complete absence of the cerebral cortex. We present the sonographic evolution of a case of fetal hydranencephaly from 11 weeks of gestation to term. At 11 weeks, the fetal head appeared small and the forehead was sloping. The normal cerebral hemispheres could not be identified. Follow-up sonography showed that the cerebral hemispheres were almost entirely replaced by fluid, except in the occipital region. The baby died 2 weeks after birth. Post-mortem examination confirmed the diagnosis of hydranencephaly.

To examine the performance of screening for pre-eclampsia (PE) and gestational hypertension (GH) by a combination of maternal factors and various biophysical and biochemical markers at 11-13 weeks' gestation. This was a case-control study of 26 cases of early PE, 90 of late PE, 85 of GH and 201 unaffected controls. Maternal history was recorded, the uterine artery with the lowest pulsatility index (L-PI) and mean arterial pressure (MAP) were measured and stored plasma and serum were analyzed for placental growth factor (PlGF), inhibin-A, activin-A, tumor necrosis factor receptor-1, matrix metalloproteinase-9, pentraxin-3 and P-selectin. Multivariate logistic regression analysis demonstrated that significant prediction for early PE was provided by maternal factors, MAP, uterine artery L-PI and serum PlGF. Significant prediction of late PE was provided by maternal factors, MAP, uterine artery L-PI, PlGF, activin-A and P-selectin. For GH significant prediction was provided by maternal factors, MAP, uterine artery L-PI and activin-A. In screening by a combination of maternal factors, biophysical and biochemical markers the estimated detection rates, at a 5% false-positive rate, were 88.5% (95% CI, 69.8-97.4%) for early PE, 46.7% (95% CI, 36.1-57.5%) for late PE and 35.3% (95% CI, 25.2-46.4%) for GH. Combined biophysical and biochemical testing at 11-13 weeks could effectively identify women at high risk for subsequent development of hypertensive disorders in pregnancy.

To investigate the development of the frontal bones and metopic suture in fetuses with trisomy 21 at 11 + 0 to 13 + 6 weeks of gestation. Three-dimensional (3D) ultrasound was used to measure the height of and gap between the frontal bones in 75 fetuses with trisomy 21 and these were compared to the measurements in 200 normal fetuses at 11 + 0 to 13 + 6 (median, 12 + 6) weeks of gestation. In the fetuses with trisomy 21, compared to the normal fetuses, there was no significant difference in either the height of the frontal bones (mean difference 0.16 SD, range -1.78 to 2.17 SD; P = 0.369) or the gap between them (mean difference 0.012, 95% CI -0.073 to 0.097; P = 0.780). Additionally, within the group of trisomy 21 fetuses there were no significant differences in the development of the frontal bones and metopic suture between those with absent (n = 46) and those with present (n = 29) nasal bone. In trisomy 21 the development of the frontal bones and metopic suture is as normal and is independent from the development of the nasal bones.

We describe a case series of six fetuses with open spina bifida (OSB) from four different prenatal units, where the anomaly was detected at the routine 11-13-week ultrasound examination. Crown-rump length ranged from 49 to 78 mm. All cases were first suspected during nuchal translucency thickness measurement in the mid-sagittal plane of the face. OSB was lumbosacral in five fetuses and cervical in one. The intracranial translucency (IT) was obliterated in two cases, but some fluid was found in the other four cases. However, in all cases the typical landmarks of a normal posterior brain and normal IT were absent. In all six cases the ratio of brainstem diameter to brainstem-occipital bone distance was increased (≥ 1). This detection of an abnormal posterior brain led to a targeted examination and detection of the spinal lesion during the same examination in five cases, whereas in one suspicious case the patient was recalled at 17 weeks, when the abnormality was detected. Two fetuses had both multiple anomalies and trisomy 18. These prospective cases demonstrate the feasibility of using the standard mid-sagittal plane commonly used for NT measurement to assess the IT and the posterior brain and to determine the presence of OSB during NT screening.

To define the relative position of the maxilla and mandible in fetuses with trisomy 18 at 11 + 0 to 13 + 6 weeks of gestation. A three-dimensional (3D) volume of the fetal head was obtained before karyotyping at 11 + 0 to 13 + 6 weeks of gestation in 36 fetuses subsequently found to have trisomy 18, and 200 chromosomally normal fetuses. The frontomaxillary facial (FMF) angle and the mandibulomaxillary facial (MMF) angle were measured in a mid-sagittal view of the fetal face. In the chromosomally normal group both the FMF and MMF angles decreased significantly with crown-rump length (CRL). In the trisomy 18 fetuses the FMF angle was significantly greater and the angle was above the 95(th) centile of the normal range in 21 (58.3%) cases. In contrast, in trisomy 18 fetuses the MMF angle was significantly smaller than that in normal fetuses and the angle was below the 5(th) centile of the normal range in 12 (33.3%) cases. Trisomy 18 at 11 + 0 to 13 + 6 weeks of gestation is associated with both mid-facial hypoplasia and micrognathia or retrognathia that can be documented by measurement of the FMF angle and MMF angle, respectively.

To determine whether in fetuses with open spina bifida at 11-13 weeks' gestation the frontomaxillary facial angle is decreased. The frontomaxillary facial angle was measured in 20 fetuses with open spina bifida and in 100 normal controls matched for crown-rump length (CRL) at 11 + 0 to 13 + 6 weeks and the values in the two groups were compared. In the control group the frontomaxillary facial angle decreased significantly with CRL from a mean of 84.0 degrees at a CRL of 45 mm to 76.5 degrees at a CRL of 84 mm (SD, 3.26 degrees). In the spina bifida group the mean frontomaxillary facial angle, corrected for CRL, was 9.9 degrees lower than in the controls and it was below the 5(th) centile in 18 (90%) of the cases (P < 0.0001). In fetuses with open spina bifida at 11-13 weeks' gestation the frontomaxillary facial angle is decreased and this measurement may be useful in early screening for this abnormality.

To compare the placental volume at 11 + 0 to 13 + 6 weeks' gestation between singleton and multiple pregnancies and to examine the possible effect of chorionicity on placental volume. The placental volume was measured by three-dimensional (3D) ultrasound using the Virtual Organ Computer-aided AnaLysis (VOCAL) technique in 290 consecutive twin and 37 triplet pregnancies at 11 + 0 to 13 + 6 weeks of gestation. For the comparison of twin, triplet and singleton placental volumes each measurement was expressed as a multiple of the median (MoM) for singletons, previously established from the study of 417 normal fetuses at 11 + 0 to 13 + 6 weeks of gestation. Median twin and triplet placental volumes were 1.66 and 2.28 MoM for singletons, respectively. In twins the placental volumes increased significantly with gestation from a median of 83.6 mL (5th and 95th centiles: 56.0 mL and 124.9 mL) at 11 + 0 weeks to 149.3 mL (5th and 95th centiles: 100.0 mL and 223.1 mL) at 13 + 6 weeks. The median MoM in monochorionic twins was not significantly different from that in dichorionic twins with fused placentas or dichorionic twins with separate placentas. In triplets the placental volumes increased significantly with gestation from a median of 114.9 mL (5th and 95th centiles: 77.6 mL and 170.1 mL) at 11 weeks to 217.9 mL (5th and 95th centiles: 147.2 mL and 322.5 mL) at 13 + 6 weeks. There were no significant differences in total placental volume between monochorionic and dichorionic triplets, monochorionic and trichorionic triplets, or dichorionic and trichorionic triplets. Placental volume in multiple pregnancies does not depend on chorionicity, and the rate of placental growth between 11 and 13 + 6 weeks is not significantly different between singletons, twins and triplets. Moreover, for a given gestational age the placental volume corresponding to each fetus in twins and triplets is 83% and 76%, respectively, of the placental volume in singletons.

Numerous studies have been performed on the accuracy of chorionicity determination, showing high accuracy of the first and the early first trimester scan (7,8,9,10). However, the majority of these studies have been conducted in large tertiary centres, whilst the current practice is that most women with twin pregnancy are first scanned by obstetricians and midwifes-sonographers in the first level ultrasound units and later referred to a specialised centre for follow-up, notably in case of monochorionicity.

To investigate the performance of first-trimester screening for aneuploidies by including assessment of tricuspid blood flow in the combined test of maternal age, fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein A (PAPP-A). Screening by the combined test was performed in singleton pregnancies, including 19 614 with chromosomally normal fetuses or the delivery of a phenotypically normal baby (euploid group), 122 with trisomy 21, 36 with trisomy 18, 20 with trisomy 13 and eight with Turner syndrome. In all cases tricuspid flow was assessed to determine if there was tricuspid regurgitation. We examined the performance of two screening strategies: firstly, assessment of tricuspid flow in all patients and secondly, first-stage screening using the combined test in all patients followed by second-stage assessment of tricuspid flow only in those with an intermediate risk of 1 in 51 to 1 in 1000 after the first stage. Tricuspid regurgitation was observed in 0.9% of the euploid fetuses and 55.7%, 33.3% and 30% of the fetuses with trisomies 21, 18 and 13, respectively, and in 37.5% of those with Turner syndrome. In a screening policy based on maternal age, fetal NT, FHR, serum free beta-hCG and PAPP-A, for a fixed false positive rate of 3% the standardized detection rates were 91% for trisomy 21 and 100% for trisomy 18, trisomy 13 and Turner syndrome. Assessment of tricuspid flow in all pregnancies would increase the detection rate of trisomy 21 to 96%, and the detection rates of trisomy 18, trisomy 13 and Turner syndrome would be 92%, 100% and 100%, respectively. The same detection rates were achieved with the two-stage strategy-in which it was necessary to assess tricuspid flow in only 15% of the total population-at a false positive rate of 2.4%. Assessment of tricuspid flow improves the performance of first-trimester screening for trisomy 21.

To establish the potential role of three-dimensional (3D) power Doppler evaluation of the placental circulation in aneuploidy screening at 11 to 13 + 6 weeks of gestation. 3D power Doppler ultrasound examination of the placenta was performed in 25 pregnancies with fetuses with abnormal karyotype and in 100 control pregnancies at 11 to 13 + 6 weeks of gestation. Using the same pre-established settings for all cases, the vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were calculated for the whole placenta. In the chromosomally normal group all the vascular indices increased significantly with advancing gestation between 11 and 13 + 6 weeks (VI: r = 0.482, P < 0.001; FI: r = 0.295, P = 0.0029; VFI, r = 0.484, P < 0.001). In the chromosomally abnormal group, the flow indices were not significantly different from normal in cases with trisomy 21 (13 cases), but they were significantly reduced compared with normal in cases with trisomies 13 and 18 (VI: t = 8.321, P < 0.0001: FI: t = 12.934, P < 0.0001; VFI: t = 7.608, P < 0.0001). 3D power Doppler evaluation of the placental circulation is not useful in screening for trisomy 21, and unlikely to further increase the already high detection rate for trisomies 13 and 18. However, we provide normal ranges of placental vascular indices between 11 + 0 and 13 + 6 weeks of gestation, which may be useful in future research on placental vascularity in certain at-risk pregnancies.

To examine the value of uterine artery Doppler at 11-14 weeks of gestation in the identification of women at risk of developing pre-eclampsia and fetal growth restriction. Uterine artery Doppler was carried out at 11-14 weeks in 3324 consecutive singleton pregnancies attending for routine care in three London hospitals. The right and left uterine arteries were identified using color flow mapping and velocity waveforms were obtained using pulsed Doppler. The mean pulsatility index of the two arteries was determined and the predictive value of a mean pulsatility index > the 95th centile in the prediction of pre-eclampsia and/or fetal growth restriction was calculated. Satisfactory flow velocity waveforms were obtained from both uterine arteries in 3195 (96.1%) of the 3324 pregnancies examined and complete outcome information was obtained for 3045 (95.3%) of these women. The 95th centile of the uterine artery mean pulsatility index was 2.35 and did not change significantly with gestational age. The pregnancy was complicated by pre-eclampsia in 63 (2.1%) cases and by fetal growth restriction in 290 (9.5%) cases. The sensitivity of a mean pulsatility index > 2.35 for pre-eclampsia (with or without fetal growth restriction) was 27.0% but for fetal growth restriction alone it was 11.7%. The respective sensitivities for these complications requiring delivery before 32 weeks of gestation were 60.0% and 27.8%, respectively. Uterine artery Doppler at 11-14 weeks of gestation identifies a high proportion of women who develop severe pre-eclampsia and/or fetal growth restriction.

To investigate the possible association between a particular pulsed Doppler waveform pattern, mitral gap, and trisomy 21 at 11 + 0 to 13 + 6 weeks. We performed two studies. The first was a retrospective analysis of pulsed Doppler velocity waveforms of the mitral valve inflow, recorded during specialist fetal echocardiography in 291 chromosomally normal and 144 trisomy 21 fetuses with a nuchal translucency (NT) thickness of 3.5 mm or more. We examined each waveform in each trace to determine whether there was a gap between the E-wave (early diastolic filling) and A-wave (atrial contraction) in the waveform across the mitral valve. We also examined each trace that contained at least one waveform with a mitral gap and, first, noted the order of waveforms with a mitral gap relative to those without and, second, measured the A-wave peak velocity in a representative waveform with a mitral gap and in one without. The second study was a prospective investigation in which Doppler velocity waveforms of the mitral valve inflow were assessed in 227 singleton pregnancies immediately before chorionic villus sampling. A mitral gap was observed in 16 (5.5%) of the chromosomally normal and in 25 (17.4%) of the trisomy 21 fetuses. The incidence of mitral gap was significantly associated with the presence of cardiac defects but not with thickness of NT. The median number of waveforms per recorded image was 6 (range, 3-7) and in 32 (78%) of the 41 traces with a mitral gap only one or two of the waveforms was abnormal. The abnormal waveforms were in the middle or at the end of the trace in 95% of cases and had a lower mean A-wave peak velocity than did the normal waveforms (mean difference 3.7 cm/s; 95% CI, 0.3-7.0 cm/s; P = 0.03). In a prospective study of 10 normal fetuses we could produce a mitral gap deliberately by moving the sample volume out of the center of flow in the atrioventricular valve. In the prospective study of 227 pregnancies undergoing chorionic villus sampling a mitral gap was observed in 26/197 (13.2%) in which the fetal karyotype was subsequently found to be normal, 4/20 (20%) with trisomy 21 and 1/10 with other chromosomal defects. At 11 + 0 to 13 + 6 weeks, a mitral gap may be more common in fetuses with trisomy 21 than in fetuses with a normal karyotype. However, it is possible that a mitral gap does not reflect an underlying hemodynamic abnormality, but is rather the result of suboptimal positioning of the Doppler sample volume as the fetus moves during acquisition.

To determine the value of measuring fetal ear length at 11-14 weeks of gestation in screening for chromosomal defects. The fetal ear length was measured in 450 fetuses immediately before chorionic villus sampling for karyotyping at 11-14 weeks of gestation. The median gestational age was 12 (range, 11-14) weeks. The fetal ear was successfully examined in all cases. The fetal karyotype was normal in 409 cases and abnormal in 41, including 32 cases of trisomy 21. In the chromosomally normal group the fetal ear length increased significantly with crown-rump length from a mean of 3.7 mm at 45 mm to 6.9 mm at 84 mm. In the trisomy 21 fetuses the median ear length was significantly below the normal mean for crown-rump length by 0.45 mm (P = 0.013) but it was below the 5(th) centile of the normal range in only two (6.3%) of the cases. There was no significant association between the delta score of ear length and delta nuchal translucency in either the chromosomally normal (r = - 0.015, P = 0.753) or the trisomy 21 fetuses (r = - 0.014, P = 0.94). At 11-14 weeks of gestation the ear length in trisomy 21 fetuses is significantly reduced but the degree of deviation from normal is too small for this measurement to be useful in screening for trisomy 21.