CLINICAL OBSTETRICS AND GYNECOLOGY Volume 57, Number 1, 142–158 r 2014, Lippincott Williams & Wilkins

First Trimester Ultrasound Assessment for Fetal Aneuploidy JON HYETT, MD,*w RITU MOGRA, MD,*w and JIRI SONEK, MDz y *RPA Women and Babies, Royal Prince Alfred Hospital; w Discipline of Obstetrics, Gynaecology and Neonatology, Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia; z Fetal Medicine Foundation USA; and yDivision of Maternal Fetal Medicine, Wright State University, Dayton, Ohio Abstract: Screening tests for trisomy 21 have gradually become more refined and now involve complex statistical models that combine demographic, biophysical, and biochemical parameters to produce individualized risk estimates for pregnant women. An understanding of the evolution of the principles, methods, and statistical techniques applied to Down syndrome screening is valuable as these processes can be transferred to other, more prevalent, adverse pregnancy outcomes. First trimester ultrasound forms the foundation of this process. Key words: trisomy 21, fetus, ultrasound, aneuploidy

of prenatal screening and diagnostic testing. This can, in part, be explained by the fact that trisomy 21 is the commonest congenital anomaly causing neurodevelopmental handicap and by the fact that the underlying etiology of the condition is discrete, clearly established, and readily defined. The only disadvantage of invasive diagnostic testing is that these tests risk miscarriage; so clinicians prefer to screen pregnancies and identify a ‘‘highrisk’’ group, limiting the impact of complications of amniocentesis or chorionic villus sampling. Screening for trisomy 21 offers one of the earliest comprehensive examples of ‘‘personalized medicine.’’ Screening tests have gradually become more refined and now involve complex statistical models that combine demographic, biophysical, and biochemical parameters to produce individualized risk estimates for pregnant women. An understanding of the

Introduction Considering trisomy 21 is uncommon, a disproportionate amount of time and money has been spent on the development Correspondence: Jon Hyett, MD, RPA Women and Babies, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW, Australia. E-mail: jon.hyett@sswahs. nsw.gov.au The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY

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Ultrasound Assessment for Fetal Aneuploidy evolution of the principles, methods, and statistical techniques applied to Down syndrome screening is valuable as these processes can be transferred to other, more prevalent, adverse pregnancy outcomes. First trimester ultrasound forms the foundation of this process.

Value of Examining the Fetus Amniocentesis was developed soon after the underlying etiology of trisomy 21 had been recognized.1 The invasive nature of the test was immediately apparent, but the risk of miscarriage had not been quantified so the test was restricted to women of advanced maternal age, who had previously been recognized as having a higher risk of carrying an affected fetus.2 The risk of miscarriage was eventually defined through a randomized controlled trial as being 1%.3 It therefore seemed appropriate to offer amniocentesis to those women who had an age-related risk for Down syndrome above this level; limiting invasive testing to 5% of pregnancies with 30% detection of affected fetuses.4 Demographic changes mean that >20% of our population are now aged 35 years and above in pregnancy, and while a 4fold increase in invasive testing will lead to a higher detection rate for trisomy 21, many cases are unidentified and the positive predictive value of this method of screening is poor.5 Screening efficacy improved with the development of second trimester biochemistry. Biochemical markers are gestational dependent, and accurate dating, through ultrasound, improves the performance of these tests.6 As the value of anatomic and biometric ultrasound assessment was recognized, second trimester ultrasound markers of trisomy 21 were described. The most powerful of these appeared to be nuchal edema.7 Invasive testing was developing concurrently, with a shift of emphasis to the first trimester, through chorionic villus sampling (CVS).

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This led to the observation that women who attended for CVS on the basis of maternal age who were found to have a fetus with nuchal edema were more likely to have a fetus affected by Down syndrome.8 Although nuchal swellings in the second trimester were readily differentiated into cystic hygroma or nuchal edema, with an inference on the type of chromosomal abnormality, these were not as important in the first trimester fetus, where the major factor that was predictive of aneuploidy was the thickness of the nuchal swelling, not its subjective appearance.9–11 The term ‘‘nuchal translucency’’ was derived to define the echolucent space seen at the nape of the neck during the first trimester scan.12

Nuchal Translucency (NT) as a Screening Tool for Aneuploidy All fetuses have a translucent area at the nape of the neck. This can be measured, with low rates of intraoperator and interoperator variability, in midsagittal section at 11 to 13+ 6 weeks’ gestation.13 NT thickness increases with gestational age, and measurements are typically expressed as a measure from the median (a delta value, Z score, or Multiple of the Median) to allow for this association.14–16 Distributions of these values have been defined in chromosomally normal and abnormal populations. In any first trimester examination, the NT thickness can be measured, adjusted for gestational age and compared to normal and trisomic distributions to develop a likelihood ratio, describing how likely it is that this fetus is chromosomally normal or abnormal. These likelihood ratios are then applied to the background level of risk to develop an individualized risk applicable to the fetus being examined.16 Accurate assessment of the risk of chromosomal abnormality is dependent www.clinicalobgyn.com

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on accurate measurement of NT, according to the standardized methodology used in the studies that defined euploid and aneuploid distributions and their related likelihood ratios.17,18 The commonest algorithm used to define risk for aneuploidy worldwide is that of the Fetal Medicine Foundation (FMF).16 Guidelines for NT measurement state that the fetus should be 11 to 13+ 6 weeks’ gestation (corresponding to a crown rump length measurement of 45 to 84 mm), should be assessed in midsagittal section imaging the fetus at high magnification so that the head and thorax of the fetus occupy at least 75% of the image, that the fetus be in a ‘‘neutral’’ position (head neither extended nor flexed), and that the nuchal translucency thickness is measured at its widest point, placing the callipers on the echogenic borders of the translucent space.14 Three measurements should be made and the largest of these used for risk calculation. Early studies reporting the screening efficacy of nuchal translucency varied widely. Two institutions in the same country reported markedly different results.19,20 Closer inspection of these studies showed that the effectiveness of screening may, in part, be dependent on the method of nuchal translucency assessment; best limited to the 11 to 13+ 6 gestational age range, defining gestational dependent ranges rather than using a fixed cut-off limit for nuchal translucency. Later studies reporting screening efficacy, that predominantly used the FMF technique, were far more consistent, showing a median 72% detection for trisomy 21 when used in isolation, and a median 87% detection for trisomy 21 when used in combination with the biochemical markers free bhCG and pregnancy associated placental protein A (PAPP-A) (Table 1).14,21–41 The most recent improvements in the performance of nuchal translucency as a screening tool for trisomies have been based on improved statistical modelling of the data rather than on changes in www.clinicalobgyn.com

measurement technique.16 Early models assumed nuchal translucency measurements were normally distributed, whereas it is now recognized that the situation is more complex and that the distribution of NT is bimodal and that likelihood ratios are best derived using a ‘‘mixture model’’ and a Baysian approach. This not only accounts for differences in the relative proportions of fetuses distributed about higher and lower NT medians, but also for differences between the various trisomies.16 The quality of NT measurements is fundamental to the success of a screening program (Fig. 1).42 Sonographers need to have formal training in nuchal translucency measurement so that they have a good understanding of the standardized technique and the importance of accurate measurements for generation of risks.43,44 Sonographers that are happy to take part in a nuchal translucency program should then submit a series of images to critical peer review—so that the quality of measurement and risk assessment is maintained. The final component of quality assurance involves regular audit, examining the distribution of nuchal translucency data for the sonographer, and providing feedback on image and measurement quality.45–48 The pathophysiology leading to increased nuchal translucency is not completely understood. It is interesting that a higher proportion of fetuses affected by trisomy 21 have an increased nuchal translucency at 11 to 13+ 6 weeks’ gestation than have nuchal edema at 18 to 20 weeks’ gestation.9,14 There is a recognized association between increased nuchal translucency and cardiac abnormalities in both chromosomally abnormal and normal fetuses.49–52 It has been suggested that fetuses with these anomalies may have some cardiac dysfunction that manifests itself through the development of subcutaneous nuchal edema at this early gestation.53 As the fetal heart continues to develop and myocardial function

Ultrasound Assessment for Fetal Aneuploidy TABLE 1.

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Studies Reporting the Effectiveness of Nuchal Translucency (NT) or Combined (NT+ bhCG + PAPP-A) First Trimester (11-13+ 6 wk’ Gestation) Assessment as a Screening Tool for Trisomy 21 Maternal Age+ NT

References

Snijders et al14 Zoppi et al21 Gasiorek-Wiens et al22 Crossley et al23 Jacques et al24 Wald et al25 Spencer et al26 Malone et al27 Monni et al28* Avgidou et al29 Saltvedt et al30 MacRae et al31 Okun et al32 Kagan et al33 Schaelike et al34 Sahota et al35* Conner et al36 Yeo et al37* Ghaffari et al38 Peuhkurinen et al39 Berktold et al40 Total

N

96,127 10,111 21,959 17,229 16,003 47,053 15,030 38,167 16,654 30,564 16,577 18,965 14,487 19,614 10,668 10,854 20,710 12,585 13,706 27,144 14,862 489,069

Maternal Age+ NT+ bhCG+ PAPP-A

Detection Rate (%)

False-positive Rate (%)

Detection Rate (%)

False-positive Rate (%)

71.8 81.3 82.9 54.0 — — 76.0 80.4 75 81.6 71.0 70.3 — 82.0 55.9 69.0 75.0 67.7

4.4 5.1 8.0 5.0 — — 5 8.4 5.1 5.0 3.5 3.2 — 5.3 5.2 5.0 5.9 5.0

— — — 82.0 90.5 83.0 92.0 86.0

— — — 5.0 3.9 5.0 5.2 5.6

65.8 69.3 54.0%-82.9%

5.0 3.6 3.2%-8.4%

90.3 — — 83.9 93.0 88.1 88.0 88.0 87.1 93.8 75.0 85.1 75.0%-93.8%

5.0 — — 4.0 5.3 4.9 5.0 6.0 5.1 4.8 4.7 4.7 3.9%-6.0%

Only studies that screened >10,000 patients are included. *NT alone (not combined with maternal age).

improves, and as the placenta becomes a low-resistance circulation and circulatory after-load is reduced, cardiac performance improves and tissue edema resolves. This has a number of consequences for screening; first, nuchal translucency assessment for aneuploidy is best performed at 11 to 13+ 6 weeks’ gestation and the effectiveness of screening is reduced at later gestations. Second, nuchal translucency is also an effective screening tool for cardiac abnormalities in euploid fetuses.54

Combined First Trimester Screening Although the recent development of mixture-model risk algorithms for nuchal

translucency have improved the sensitivity and specificity of this screening tool it is important to recognize that a minority of fetuses affected by trisomy 21 will have normal nuchal translucency and will not be detected using this tool alone.16 This also applies to trisomies 18 and 13, where it is notable that while the median value of nuchal translucency for fetuses that have ‘‘high’’ nuchal translucency values is more widely deviated from the ‘‘low’’ nuchal translucency dataset, the proportion of fetuses distributed around the ‘‘low’’ nuchal translucency median is larger than is the case for trisomy 21.14,55,56 Further improvements in screening efficacy require the involvement of other markers, either derived through biochemistry or through extended ultrasound assessment. www.clinicalobgyn.com

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Hyett et al or overmeasurement of nuchal translucency, or of persistent miscalculation of biochemical MoMs, will be blunted by the use of multiple parameters.17,57

Additional Markers Being Used in Clinical Practice

FIGURE 1. A midsagittal section of a fetus at 12 weeks gestation showing the nuchal translucency thickness. Correct assessment involves clear magnification (head and thorax only) and correct placement of the callipers around the translucent nuchal space.

First trimester ultrasound screening has driven the development of first trimester biochemical markers. Although none of these markers are individually as powerful as nuchal translucency they are valuable additions to screening. Free bhCG and PAPP-A are most commonly used in conjunction with NT assessment at 11 to 13+ 6 weeks and this screening test is commonly described as combined first trimester screening. There is no apparent relationship between NT and either of these biochemical markers and independent likelihood ratios can therefore be applied to an a priori risk (based on maternal and gestational age) for all 3 screening factors. Several large studies have reported the effectiveness of combined first trimester screening (Table 1).23–40 Inclusion of biochemistry seems to improve the sensitivity of screening by approximately 10% for the same level of specificity. One of the attractions of the combination of these markers is that the test is more robust from a quality assurance perspective; the potential effects of consistent undermeasurement www.clinicalobgyn.com

Combined first trimester screening offers a robust tool for the detection of common fetal aneuploidy. The specificity of this test could, however, be improved by the addition of extra biochemical or ultrasound markers. Adding extra ultrasound markers at 12 weeks has the advantage that all test data are collected simultaneously and an immediate result can be given. These tools also provide clinicians in the developing world where biochemistry is often prohibitively expensive, with a means of improving their screening efficiency. There are 3 additional ultrasound markers that are currently commonly used to improve the performance of first trimester screening with nuchal translucency: echogenicity of the nasal bone, the pattern of blood flow through the ductus venosus and fetal heart rate. Langdon Down’s original phenotypic description of trisomy 21 includes the report that these children appeared to have a small nose.58 These abnormalities can been seen sonographically and were first recognized in populations examined at 18 to 20 weeks’ gestation.59 Although the second trimester assessment of the nasal bone is centered on identification and measurement of nasal bone length, first trimester (11 to 13+ 6 wk) assessment is focused on sonographic appearance.60,61 A normal nasal bone can be clearly visualized in midsagittal section and is described as being more echogenic than the skin line above it. An ‘‘absent’’ nasal bone is either not visible, or is less echogenic than the skin line above it (Fig. 2).62 Several studies have now reported the prevalence of the finding of an

Ultrasound Assessment for Fetal Aneuploidy

FIGURE 2. A midsagittal section of a 12-week fetus demonstrating an absent nasal bone. The nasal bone should be more echogenic than the skin edge at the apex of the nose.

‘‘absent’’ nasal bone in chromosomally normal and abnormal populations (Table 2).28,63–76 Although there is some association with gestational age, ethnic origin, and nuchal translucency thickness, this finding is uncommon in euploid fetuses and this is a very specific screening tool.77 Categorization of the nasal bone as been ‘‘present’’ or ‘‘absent’’ has a

TABLE 2.

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significant effect on the ascribed risk of trisomy 21—decreasing risk 3-fold and increasing risk 24-fold, respectively.77 As a consequence, trisomic fetuses with normal nuchal translucency may be redefined as being high risk, whereas normal fetuses with borderline high risk (eg, women of advanced maternal age with a high a priori risk) NT may be redefined as being low risk. The addition of nasal bone to the combined first trimester screening algorithm improves both sensitivity and specificity of the test.37,69,78 There are, however, some problems with the introduction of nasal bone assessment as an additional marker in all examinations. Nasal bone assessment is generally found to be technically more difficult than nuchal translucency assessment and it has been shown that it takes a competent sonologist up to 120 examinations to reach a point of proficiency where the nasal bone can be assessed in all cases.79 Second, the findings are more subjective than the measurement of nuchal translucency and as they are categorical they lead to very dramatic swings in risk, which makes

Screening Studies Looking at the Prevalence of an Absent/Hypoplastic Nasal Bone in First Trimester Fetuses

References

Orlandi et al64 Viora et al65 Zoppi et al66 Malone et al67 Orlandi et al68 Monni et al28* Cicero et al69 Prefumo et al70 Ramos-Corpas et al71 Sepulveda et al72 Moon et al73 Has et al74 Leung et al75 Kagan et al76 Total

N

1089 1906 5532 6324 2411 16654 20418 7116 1800 1287 6787 1816 8101 19788 100977

Prevalence

Unsuccessful Assessment [n (%)]

Detection Rate for Trisomy 21 [n/n (%)]

1 in 73 1 in 191 1 in 204 1 in 702 1 in 161 1 in 173 1 in 146 1 in 593 1 in 300 1 in 42 1 in 452 1 in 202 1 in 311 1 in 162 1 in 189

62 (5.7) 154 (8.1) 7 (0.2) 1523 (24.1) — 13 (0.1) 243 (1.2) 712 (10.0) 118 (6.6) 0 (0) 297 (4.37) 9 (0.5) 176 (2.2) 52 (0.25) 3366 (3.3)

10/15 (66.7) 8/10 (80) 19/27 (70) 0/9 (0) 8/15 (53.3) 56/96 (58.3) 87/140 (62.1) 2/12 (16.7) 2/6 (33.3) 13/31 (41.9) 8/15(53.3) 3/9 (33.3) 13/26 (50) 73/122 (59.8) 302/533 (56.7)

False-positive Rate [n/n (%)]

10/1,000 (1.0) 24/1733 (1.4) 7/3463 (0.2) 21/4790 (0.4) 9/2396 (0.4) 76/16513 (0.5) 113/20165 (0.6) 172/6354 (2.7) 19/1790 (1.1) 2/1221 (0.2) 16/6456 (0.2) 7/1792 (0.4) 164/7899 (2.1) 513/19614 (2.6) 1153/95186 (1.21)

*Also had publication in 2002 that appears to involve part of this study group.

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many sonographers nervous about the interpretation of their data. This has meant that incorporation of nasal bone assessment has been slower than would have been anticipated on the basis of the data demonstrating the power of the marker and is often restricted to practices that screen large number of patients. The pathologic and molecular identification of an association between increased nuchal translucency and structural and functional cardiac defects has already been described. These changes in cardiac performance may also be defined sonographically. The first trimester fetal heart has little myocardial compliance, and changes in cardiac output are dependent on variation of heart rate.80 Early studies showed that the heart rate peaks in euploid fetuses at 10 to 11 weeks gestation and then falls through the 11 to 13+ 6 week gestational period.81 Fetal heart rate is significantly higher in fetuses with trisomy 21 and trisomy 13 and significantly lower in fetuses with trisomy 18.81 This change is most significant in trisomy 13 and the current FMF algorithm restricts the use of fetal heart rate to generation of risks for trisomy 13.82 A high heart rate (>95th centile) increases the risk for trisomy 13, whereas a normal heart will reduce the risk for this aneuploidy. The overall effect of inclusion of this parameter is to increase the sensitivity of combined first trimester screening for trisomy 13 while minimizing the false-positive rate associated with this trisomy. As a high heart rate will have a significant impact on risk, it is important to take care when assessing the rate. This is best done at the beginning of the first trimester evaluation, measuring heart rate over several cardiac cycles to minimize measurement error. If the heart rate is high then the assessment should be repeated at the end of the scan—the rationale being that the trisomic fetus likely has some autonomic dysfunction that has an impact on the heart rate, which will be consistently high www.clinicalobgyn.com

rather than been affected by other factors such as fetal activity. The ductus venosus can also be used as a sonographic tool for assessment of cardiac function. In a series of 486 women attending for CVS after first trimester screening the ductus venosus was assessed before karyotyping. 90.5% of fetuses that had a chromosomal abnormality had an absent or reversed ‘‘A’’ wave in the ductus venosus compared with 3.1% who had a chromosomally normal fetus (Fig. 3).83 Interestingly 7/13 (54%) chromosomally normal fetuses with an abnormal ductus venosus waveform were later found to have a cardiac defect. The ductus venosus is best assessed using color Doppler to visualize the vessel in a right parasagittal section.84 The probe should be rotated to reduce the angle of insonation for Doppler sampling to 50% of the cardiac cycle.

velocity of 80 cm/s for at least 50% of systole (Fig. 4). Two larger prospective studies involving high-risk cohorts (attending for early fetal echo assessment or for CVS) demonstrated that the flow across the tricuspid valve could be successfully assessed by multiple operators in >96% of cases.99,100 Tricuspid regurgitation affected 65% of fetuses with trisomy 21 and 53% of those with trisomies 18 or 13 and was more likely to be found in euploid fetuses examined at earlier gestations or with increased nuchal translucency. Risks of both trisomy 21 and trisomy 18 were described by likelihood ratios that were adapted to account for gestational age and fetal NT thickness. The overall positive and negative likelihood ratios for trisomy 21 were 7.7 and 0.38, respectively. Analysis of a cohort of fetuses undergoing combined first trimester screening found no association between tricuspid regurgitation and either free bhCG or PAPP-A and suggested that screening using an algorithm that included tricuspid regurgitation in addition to NT, free bhCG, and PAPP-A would allow detection of 90% of fetuses affected by trisomy 21 for a 2% to 3% false-positive rate.101 An alternative method of including data

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on tricuspid regurgitation, in a contingent manner for fetuses with an intermediate risk of 1 in 100 to 1 in 1000 after traditional combined first trimester screening has been estimated to detect 91.7% of trisomy 21 fetuses for a 2.7% false-positive rate. This level of screening performance has, more recently, been validated in a prospective study of 19,614 women attending for combined first trimester screening.102 ABERRANT RIGHT SUBCLAVIAN ARTERY

The association between trisomy 21 and cardiac defects was not clearly recognized until 1898. Most of the early series describing cardiac anomalies in fetuses affected by this chromosomal abnormality focus on intracardiac anomalies, but a thorough review of the literature published in 1960 reported 2 cases of isolated aberrant right subclavian artery.103 Subsequent review of a series of infants affected by trisomy 21 that had been investigated by angiography found that 16/45 (36%) of these infants had an aberrant right subclavian artery, arising as the last branch of the aortic arch.104 These findings are almost identical to those described in second and third trimester fetuses where the course of vasculature can be described using color Doppler ultrasound.105 The right subclavian artery is normally recognized by moving the ultrasound probe cranially from the axial view of the transverse arch view (Fig. 5). When the vessel is aberrant it is seen arising directly from (and therefore at the level of) the transverse arch, at the apex of the confluence of the aortic and ductal arches, running across the midline behind the trachea. An improvement in the ultrasound technologies has allowed earlier assessment of the course of the right subclavian artery using color Doppler. Zalel et al106 reported the ultrasound findings of a series of 924 fetuses examined at 13 to 26 weeks’ gestation. An aberrant right

FIGURE 5. An aberrant right subclavian artery seen in this transverse section of the thorax at 12 weeks gestation.

subclavian artery was seen in 1.4% of normal and 37.5% of trisomy 21 fetuses. The 3 trisomy 21 cases that had an aberrant right subclavian artery all had other anomalies described. A second study performed in the second trimester (>16 wk gestation) similarly described an aberrant right subclavian artery in 1.1% of normal and 35% of Down fetuses.107 The positive and negative likelihood ratios for Down syndrome in the presence/absence of this finding were calculated as 45.1 and 0.65, respectively. In a prospective study of 516 high risk first trimester (11+ 0–13+ 6 wk’ gestation) pregnancies, the right subclavian artery could be identified in 82% of cases.108 An aberrant course was described in 0.6% of euploid and 7.8% of trisomy 21 fetuses. An aberrant course was also demonstrated in 10% of fetuses with other chromosomal abnormalities. This study demonstrated that including assessment of the right subclavian artery at 11 to 13+ 6 weeks was feasible, although imaging was hindered by early gestation or high maternal BMI. In comparison to other markers, an aberrant www.clinicalobgyn.com

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right subclavian artery is less prevalent in chromosomally abnormal populations so this is unlikely to be valuable as a primary marker in screening for aneuploidy. It is also a relatively poor marker for structural cardiac abnormalities; in 1 series only 2.9% of fetuses with an aberrant right subclavian artery had a concurrent cardiac anomaly.109

Detecting Structural Anomalies, and their Significance From the Perspective of Aneuploidy Screening Traditional markers of aneuploidy that are used in the second trimester of pregnancy have not been extensively investigated at 11 to 13+ 6 weeks gestation. This is in part because many of the structures examined at 20 weeks are less developed at 11 to 13+ 6 weeks, and in part because the likelihood ratios ascribed to nuchal translucency, nasal bone, and the ductus venosus are much stronger. Dagklis and colleagues found that echogenic foci, pyelectasis, and hyperechogenic bowel are more prevalent in trisomy 21 than in euploid fetuses.110 The prevalence of choroid plexus cysts was not significantly different. On occasion, a structured anatomic survey will reveal the presence of a major structural anomaly at the time of the 12week scan. Several of these anomalies are recognized as having significant associations with aneuploidy. Holoprosencephaly is strongly associated with trisomy 13, and the prevalence of aneuploidy is in fact higher in fetuses affected by holoprosencephaly at 12 weeks than at term as a significant proportion of the aneuploid fetuses will die in utero.111 Although acrania and spina bifida are frequently isolated structural abnormalities they are also associated with chromosomal abnormality, most commonly trisomy 18, and karyotyping is worthwhile as this will www.clinicalobgyn.com

have an impact on risks for future pregnancies.112 An omphalocoele is also associated with trisomy 18, and this needs to be carefully assessed as many of those linked to aneuploidy are small and relatively subtle at 12 weeks.113 An enlarged bladder (megacystis) is recognized as being associated with both trisomy 21 and trisomy 13.114 Likelihood ratios can be ascribed to all of these features, and a low threshold for karyotyping should be considered.115

The Other Advantages of Ultrasound First trimester screening is a highly effective means of screening for Down syndrome, surpassing previous methods of assessment based on maternal age alone, the use of second trimester serum markers, and of second trimester ultrasound assessment. Consequently, in many jurisdictions, the first trimester scan is now incorporated as a routine part of pregnancy management.116–118 The real benefit lies beyond screening for either chromosomal or structural anomalies and there is growing evidence that a routine first trimester ultrasound can have

FIGURE 6. Defining placentation is probably the most important aspect of a 12-week scan in twins. Here, the thin intermembrane inserts as a ‘‘T’’ into the placenta—evidence of monochorionic diamniotic placentation.

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to recognize the much wider role that routine ultrasound screening now plays and the impact this is having on perinatal outcomes.

Conclusions: First Trimester Ultrasound in the Era of ‘‘Noninvasive Prenatal Screening’’ FIGURE 7. The uterine artery is assessed as part of the screening protocol for predicting preeclampsia and/or intrauterine growth restriction. The waveform is commonly notched in the first trimester and pulsatility indices are used to calculate risks.

a significant impact on a number of obstetric outcomes. Most simply, accurate pregnancy dating by measurement of crown rump length in early pregnancy reduces the rate of postdate inductions by 15%.119 Identification of twin pregnancies at this early stage allows reliable determination of chorionicity impacting on plans for ongoing surveillance of monochorionic twins, recognized as having significant risks of morbidity and mortality (Fig. 6).120,121 The methodology used to produce risk algorithms for prediction of aneuploidy are now been adapted for use in prediction of preeclampsia, intrauterine growth restriction, and preterm delivery (Fig. 7).122–124 The model predicting the risk of preeclampsia is most advanced, and we have recently validated this in a prospective observational study.125 This is particularly promising as intervention (aspirin treatment) is cheap, has minimal risk to the pregnancy and, when started at early gestations, seems to have a significant impact on disease prevalence.126 Although first trimester screening had its foundations in screening for aneuploidy, it is important

Recent advances in molecular genetics have led to the development of highly sensitive, highly specific methods of defining fetal karyotype through analysis of cell-free DNA. Current guidelines suggest these tests should be offered to women at high risk for aneuploidy, but there are 2 issues with this approach.127 First, use as a secondary screening tool negates the advantage of this technology, as the overall sensitivity of screening will be dependent on first-line assessment. Second, some high-risk women would be better advised to have an invasive test, as noninvasive techniques do not identify all atypical chromosomal abnormalities that account for 20% of detected aneuploidy.128 One alternative strategy that has been proposed involves incorporation of cellfree DNA into a ‘‘combined’’ first trimester screening protocol while another involves offering cell-free DNA testing on a contingent basis.129–131 Both of these routes have the advantage of continuing to offer ultrasound surveillance at 12 weeks, which should be considered to be a cornerstone of obstetric care.132

References 1. Richards BW, Stewart A, Sylvester PE, et al. Cytogenetic survey of 225 patients diagnosed clinically as mongols. J Ment Defic Res. 1965;9: 245–259. 2. An assessment of the hazards of amniocentesis. Report to the Medical Research Council by their Working Party on Amniocentesis. Br J Obstet Gynaecol. 1978;85 (suppl 2):1–41.

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