REVIEW URRENT C OPINION
Soft markers for aneuploidy following reassuring first trimester screening: what should be done? Vedran Stefanovic
Purpose of review The present article aims to review the current role of the soft markers on the second trimester ultrasound (STUS) in women after reassuring first trimester screening (FTS) in singleton pregnancies. Recent findings Improvements in the FTS and the recent implementation of noninvasive prenatal testing (NIPT) for common aneuploidies have important impact on the prevalence of these conditions in the STUS. Some studies suggest that soft markers in the second trimester of the fetus without structural anomalies have a minor or no role in Down syndrome detection in a prescreened population with reassuring results. However, NIPT could be offered as a next step in the management of such pregnancies if the calculated new composite risk (NCR) for aneuploidy is increased. In the case of reassuring results, pregnancy follow-up for certain markers is advised. Summary NIPT has emerged as a new method of prenatal testing and is feasible in the second trimester in women with increased NCR. However, apart from the Down syndrome screening, STUS screening remains a powerful tool in screening for other fetal aneuploidies, structural anomalies and pathological placental conditions and detection of specific soft markers that require pregnancy follow-up. Keywords aneuploidy, counseling, noninvasive prenatal testing, screening, soft markers
INTRODUCTION Ultrasonography for aneuploidies and fetal structural anomaly screening in the second trimester of pregnancy (STUS) during week 18–20 was introduced into clinical practice almost 3 decades ago. A number of sonographic findings, known as soft markers, are often found in aneuploid fetuses (mostly in Down syndrome) and those with structural anomalies, although they are usually found as normal variants in a substantial proportion of euploid fetuses without structural anomalies. Despite the benefits of STUS, false-positive findings indisputably cause parental anxiety and amniocentesis for fetal cytogenetics is usually offered. The study of Boyd et al. [1] has assessed the effect of the detection of ultrasonographic soft markers on the efficacy of prenatal screening programmes reporting that for a 4% increase in the detection rate of congenital abnormalities (from 51 to 55%), there was a 12-fold increase in false-positives leading to the decrease in the specificity of STUS. Based on this report, concerns about the resource implications, risk of procedure-related normal pregnancy
losses and the short and long-term psychological sequelae arose. The list of soft markers has been going through extensive changes in recent years, with certain new markers added, whereas some have virtually disappeared. The commonly studied soft markers of aneuploidy include a thickened nuchal fold, short long bones (SLBs), mild fetal pyelectasis, echogenic intracardiac focus (EIF), absent or hypoplastic nasal bone and hyperechogenic bowels. Additionally, some researchers consider fetal venticulomegaly as an anomaly, and others include it in the list of soft markers. Finally, isolated single umbilical artery
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Corresponding to Vedran Stefanovic, A/Professor of Obstetrics, Gynecology and Fetomaternal Medicine, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 2, PL 140, 00029 HUS Helsinki, Finland. Tel: +358 50 427 1230; e-mail: vedran. [email protected] Curr Opin Obstet Gynecol 2015, 27:151–158 DOI:10.1097/GCO.0000000000000157
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KEY POINTS Soft markers at the STUS after reassuring FTS have limited value, but their presence may increase slightly the detection rate of Down syndrome. NIPT may be a feasible management option for women with NCR at STUS after presence of any soft marker or those with any combination of two soft markers. Soft markers in structurally normal euploid (or presumably euploid) fetuses have weak association with adverse pregnancy outcome. Pregnancy follow-up for specific soft markers is required, but the pregnancy outcome and the long-term outcome of such pregnancies are generally favorable. Despite widespread implementation of NIPT, ultrasound screening in the first and second trimester will remain the powerful obstetrical tool for screening of aneuploidies, structural abnormalities and pregnancy complications.
(iSUA) and choroid plexus cyst (CPC) are still attracting attention on the STUS, although they are not considered any more as soft markers. Screening for Down syndrome and other aneuploidies has been shifted from the second to the first trimester [2]. Before the introduction of noninvasive prenatal testing (NIPT), the most accurate screening test was first trimester combined screening (FTS), which is a combination of maternal age, fetal nuchal translucency and serum biochemistry achieving detection rate of 90% and 5% false-positive rate (FPR) [3 ]. FTS has provided ability for not only early detection of aneuploidies, but also severe congenital anomalies [4] and enabled early and safer pregnancy termination, if required. Recently published meta-analysis of the screening performance of the soft markers for trisomy 21 that included 48 studies concluded that their presence increased, and their absence decreased the risk for trisomy 21 [5 ]. As soft markers were introduced in obstetrical practice as promising markers for aneuploidy (almost exclusively for Down syndrome) in highrisk population and were not properly validated [6], there have been efforts for clarification of their significance after normal FTS. Additionally, the literature concerning need for follow-up of pregnancies with certain euploid fetuses is rather confusing [7 ]. The present article aims not only to review recent literature about the current role of the soft markers on the STUS in women after reassuring FTS, but to propose a simplified flow-chart for the &&
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management of such pregnancies (Fig. 1). Additionally, a summary of the pregnancy follow-up for specific soft markers is provided (Table 1).
STUDIES ON THE UTILITY OF SECOND TRIMESTER SCREENING AFTER FIRST TRIMESTER SCREENING Owing to the limited space, only few relevant studies will be included in this chapter. Although the results of some studies suggest that carefully performed STUS may improve the overall detection rate of Down syndrome after normal result on FTS, the others failed to confirm this. The simulation study of Krantz et al. [8] showed that by using individual marker likelihood ratios to modify the FTS for screen-negative patients, STUS detected an additional 6.1% of Down syndrome cases for an additional 1.2% FPR, giving a total detection rate of 94.6% and a total FPR of 5.4%. The retrospective cohort study of Sood et al. [9] included 3845 singleton pregnancies from the general population that underwent FTS followed by a STUS. Previously published likelihood ratios were used to modify each patient’s quantitative risk as ascertained by the FTS to generate a new composite risk (NCR). A fixed risk cut-off of 1/300 for Down syndrome was used for both FTS and the NCR. The principal finding of the study was that the use of soft markers may increase the positive predictive value in patients with high-risk FTS. The authors suggest that this group (particularly in the absence of major structural malformations) may benefit from the further risk adjustment at the STUS and avoid straightforward amniocentesis. On the contrary, in patients with a low risk on the FTS, the presence of soft markers did not have additional value in improving the detection rate of Down syndrome. A previously published study by Aagaard-Tillery et al. [10], which included 59 Down syndrome fetuses from 7842 pregnancies, showed an improvement in detection rate of the FTS from 88 to 95% on the STUS. The main limitation of this study is that it did not include short humerus, which has higher positive likelihood ratio than short femur (SF) (4.81 vs. 3.72). The study of Kaijomaa et al. [11 ] included 228 singleton pregnancies from the general obstetric population referred for two or more soft markers present at STUS in structurally normal fetuses with normal FTS (cutoff 1/250). Only two fetuses (0.9%) had significant aneuploidy: a case of trisomy 18 and triploidy case, respectively. There were two additional cases of chromosomal abnormalities: one case of 4% Down syndrome mosaicism (healthy euploid newborn) and clinically irrelevant case of &
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Soft markers after normal first trimester screening Stefanovic
Normal FTS*
Any SM on STUS Two or more SMs on STUS NCR generation
Increased NCR
NIPT
Normal NCR
Abnormal or no-call
Normal
Amniocentesis
Abnormal
Follow up specific SMs** *Cutoff should be determined by each expert institution ** See Table 1. FTS, first trimester screening; NCR, new composite risk; NIPT, noninvasive prenatal testing; SM, soft marker; STUS, second trimester ultrasound screening.
FIGURE 1. Proposal for the management of soft markers on second trimester ultrasound after reassuring first trimester screening.
chromosome 10 inversion with the healthy newborn, as well. Authors conclude that combination of any soft markers has very limited or no value in screening for Down syndrome in singleton pregnancies after normal FTS. However, this study did not use NCR nor the nuchal fold as a SF, which is known to have considerably high positive likelihood ratio of 23.30. The presence of three other chromosomal abnormalities than Down syndrome is in line with the results of Breathnach et al. [12] on the screening performance for detection of aneuploidies other than Down syndrome. That study used cutoff level of 1/300 for Down syndrome and 1/100 for trisomy 18. It is known that detection rate and associated FPR vary not only by screening cutoff level chosen, but also by the age distribution of the women tested, the gestational age at sampling and the
combination of markers chosen. Reports should give numerical risk, not just a screen-positive or screen-negative interpretation [13]. The study of Wax et al. [14] showed that application of STUS may lead to a very high screenpositive rate without improving the detection rate for Down syndrome. However, in this study, STUS was not performed as a universal screen on the entire population. The retrospective study of Bromley et al. [15 ] concluded that second trimester soft markers, particularly nuchal fold, are important findings in the detection of Down syndrome among fetuses who had FTS for aneuploidy. Among 42 fetuses with Down syndrome (0.4% of the cohort), there were nine fetuses who were first suspected of having aneuploidy based on the presence of soft markers without structural anomalies at STUS. Only three of
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Prenatal diagnosis Table 1. Proposal for pregnancy follow-up of specific soft markers Positive likelihood && ratio isolated [5 ]
Marker
Prenatal follow-up
Remarks
Prenatal ultrasound follow-up of fetal growth at 32 weeks of gestation, special attention to signs of gastrointestinal obstruction
Screening for perinatal infections (especially CMV) and cystic fibrosis according to the individually estimated risk
Prenatal ultrasound follow-up for fetal growth on the individual basis, screening for PIH, FGR and preeclampsia
Careful prenatal rule out of certain skeletal dysplasias (e.g. achondroplasia cases have normal femur length until >25 weeks of gestation)
Hyperechogenic bowel
11.44
Short femur length and humerus length
3.72 and 4.81
Echogenic intracardiac focus
5.83
Not justified
Diffuse myocardial calcifications with specific disease and poor outcome not considered as soft marker
Fetal pyelectasis APD 4–10 mm
3.72
Prenatal follow-up at 32 weeks of gestation, if renal pelvis >7 mm, postnatal follow-up suggesteda
Postnatal cystography and other individual urologic diagnostic procedures if renal pelvis >15 mm
Ventriculomegaly
27.52
Third-level prenatal sonography for other neural and extraneural anomalies, adjunct MRI
Prenatal screening for alloimmune thrombocytopenia and prenatal infections (especially CMV). Postnatal MRI and followup should continue until development is established as normal
Isolated single umbilical artery
N/A
Not justified
Not 21-trisomy soft marker, but one of the most frequently found anomalies at time of second trimester screening. Prenatal ultrasound follow-up for fetal growth
Choroid plexus cyst
N/A
Not justified
Not 21-trisomy soft marker, but screened still in many institutions. Postnatal evaluation not indicated, since normal long-term neurodevelopmental outcome has been addressed in cases of isolated choroid plexus (discovered both prenatally and in postnatal period)
APD, anterioposterior diameter; CMV, cytomegalovirus; FGR, fetal growth restriction; PIH, pregnancy-induced hypertension. a Optionally, if renal pelvis initially 7 mm, postnatal evaluation would be more appropriate than prenatal follow-up.
them underwent combined FTS (the rest had serial sequential test), of which had normal result on the combined FTS thus being detected on the basis of soft markers. Although aforementioned studies were very different in design and with different cutoff, it seems that in pregnancies with normal or borderline result in FTS, detection of soft markers on STUS may improve detection rate of Down syndrome and some other chromosomal abnormalities in the fetuses without structural anomalies.
PREGNANCY MANAGEMENT OPTIONS AFTER DETECTION OF SOFT MARKERS AND NORMAL FIRST TRIMESTER SCREENING The ultimate goal of noninvasive screening methods is to achieve acceptable high detection rate of aneuploidies with lowest possible false-positive results avoiding invasive procedures. 154
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Women should be informed that the risk of procedure-related miscarriage following amniocentesis at a mean gestational age of 16 weeks is around 1% [16]. The large Danish cohort study of more than 60 000 singleton pregnancies showed that the postprocedural fetal loss rates after CVS or amniocentesis before 24 completed weeks’ gestation were 1.4 and 1.9%, respectively, and total fetal loss rates were 2.0 and 2.3%, respectively. The fetal loss rate figures in this study consisted of a procedure-related loss rate plus the spontaneous miscarriage rate [17]. An increasing number of studies in high-risk pregnancies reported that NIPT analysis of maternal plasma can detect more than 99% of pregnancies with fetal trisomy 21 at FPR of less than 1%, with somewhat lower performance for trisomies 18 and 13 [18 ]. The implementation of this new and rather expensive technology into routine care is complex, as the information obtained from NIPT screening may overlap or contradict that from other &&
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methods of screening such as FTS or STUS. So far, there are no studies on the implementation of NIPT in women with normal FTS and soft markers detected on the second trimester screening. The acceptable concept would be to offer NIPT to two groups of women: those having increased NCR on the second trimester screening after normal FTS (excluding structural anomalies) or to women with combination of any two soft markers at the STUS (Fig. 1). On the contrary, cutoff level for the FTS should be determined by each specialized institution and all relevant soft markers should be included in the STUS screening. Although this approach would probably have a high uptake by women with such pregnancies because of its noninvasive nature, some worrisome issues arise. Reported failure rates of NIPT vary considerably and may be up to 5% [19]. After a failed result, NIPT can be repeated, which certainly adds additional time, costs and considerable parental anxiety to the screening and diagnostic process. Women who would consider a termination of pregnancy in case of a fetus with aneuploidy should always be counseled to have amniocentesis to confirm a positive NIPT result. In many countries, pregnancy termination for fetal indication is only possible up to 24 weeks’ gestation, so the time limit is an important issue. Fortunately, rapid PCR methods for the most common aneuploidies are available and further karyotyping would find out the very small number of cases with abnormal karyotype with clinical importance [20]. Obstetrical ultrasound in the first trimester has diagnostic and screening purpose, but despite NIPT screening for common aneuploidies, the role of first trimester ultrasound and STUS will hardly be replaced in the near future. Implementation of NIPT will have substantial impact on the prevalence of aneuploidies and the screening performance of STUS, although searching for fetal structural anomalies, single-gene disorders and placental abnormalities will probably never be replaced, both in euploid pregnancies with increased nuchal translucency at the time of FTS [21 ] and those with soft markers after normal FTS or already confirmed euploid pregnancy [22 ]. STUS evaluation thus remains the accessible, cost-effective and important examination for most pregnant women in the world, especially for those in low resource setting without logistical or financial possibility of having NIPT and invasive procedures. In such conditions, it is too early to abandon ultrasonographic fetal evaluation as a powerful screening tool [23 ]. &
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DO ISOLATED SOFT MARKERS REQUIRE PREGNANCY FOLLOW-UP? Although some soft markers have no significance beyond the association with aneuploidy, a few of them have potential nonaneuploidy-related associations with the pregnancy outcome [7 ]. The next chapter will briefly discuss this issue and propose a simplified guideline for specific soft markers (Table 1). Although CPC is not associated with Down syndrome and SUA has not been considered as a soft marker for a long time, they are frequently reported and are still on the soft marker list of certain national guidelines [24]. &
HYPERECHOGENIC BOWEL The prevalence of this subjective finding on the STUS ranges from 0.2 to 1.8%. Echogenic fetal bowel may be associated with congenital viral infections, aneuploidy, intra-amniotic bleeding or cystic fibrosis, anemia or FGR. Goetzinger et al. [25] reported that even after exclusion of cases with aneuploidy and cytomegalovirus (CMV) infection, echogenic fetal bowel on ultrasound was independently associated with an increased risk for both FGR and intrauterine fetal death (IUFD). The authors thus advocate serial fetal growth assessment. However, the review article of De Oronzo [26] stressed that a reproducible definition of echogenic fetal bowel is urgently needed so that large, controlled, prospective studies with standardized equipment settings and methods of collection could ultimately replace the largely retrospective data currently available. The study of Patel et al. [27] has provided reassurance that there was no evidence of any serious longterm bowel disease associated with isolated fetal echogenic bowel.
FEMUR LENGTH AND INTRAUTERINE FETAL GROWTH RESTRICTION Fetal SLBs at the time of STUS have been associated with aneuploidy, skeletal dysplasias, fetal structural anomalies, preeclampsia, IUFD and fetal growth restriction (FGR). In the study of Todros et al. [28], 50% of the women developed preeclampsia while undergoing follow-up for SF (femur length) and FGR. A recently published Danish study, which assessed the relationship between the finding of SF at STUS and pregnancy outcome, reported that SF was associated with a significantly higher relative risk of aneuploidies, small-for-gestational age infants and early preterm delivery [29 ]. The results of Goetzinger et al. [30] are in line with the previous one. Serial growth assessment may be warranted in these cases.
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ECHOGENIC INTRACARDIAC FOCUS
SINGLE UMBILICAL ARTERY
The presence of an EIF as a soft marker for fetal aneuploidy has been reported by many studies, particularly in high-risk populations. Postnatal cardiac function after the presence of prenatally diagnosed EIF has been evaluated in several studies showing no association with myocardial dysfunction during childhood. Additionally, electrocardiographic follow-up did not show any significant abnormalities irrespective of postnatal EIF persistence or resolution. The significance of isolated EIF is discussed in detail in the review article of Rodriguez et al. [31 ].
The reported incidence of SUA varies from 0.5% after the routine postnatal examination to 5.9% in a selected high-risk population. SUA appears to be an isolated finding (iSUA) in 56% of cases. Voskamp et al. [37 ] performed a meta-analysis on the significance of iSUA in 928 pregnancies, which did not show a statistically significant difference in aneuploidy rate, birth weight and incidence of FGR between iSUA fetuses and three vessel cord fetuses. Authors concluded that targeted growth assessment after diagnosis of iSUA should not be routine practice. Additionally, the large study of Chetty-John et al. [38] failed to demonstrate any clinically significant effect of iSUA with regard to growth or neurodevelopment (follow-up 7 years).
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FETAL PYELECTASIS Fetal pyelectasis is defined as an anteroposterior measurement in a transverse scanning plane of 4 mm or larger in the second and/or 7 mm or larger in the third trimester, whereas pelvic anteroposterior diameter (APD) 10 mm or larger is criteria for hydronephorosis. Although fetal pyelectasis is usually self-limited, in some cases it can occur as true renal disease and may be associated with other fetal anomalies. There is a consensus that in the absence of other findings, isolated fetal pyelectasis is not a justification for karyotyping. The study of Odibo et al. [32] reported that the renal threshold that best predicted normal postnatal outcome was an APD of less than 7.0 mm after 32 weeks, yielding high sensitivity and specificity. John et al. [33] concluded that the dilatations of an APD larger than 4 mm, with spontaneous resolution at the post 33-week scan, need no further unnecessary postnatal investigations.
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CHOROID PLEXUS CYST CPC may be single or multiple and is identified in approximately 1 to 2% of fetuses in the second trimester usually as an isolated finding in otherwise normal low-risk pregnancy. The great majority of CPCs resolve by 28 weeks. CPC is not considered a structural nor functional brain abnormality. Cheng et al. [39] concluded that in pregnancies with isolated CPCs, fetal karyotyping is not indicated when no additional anomaly is detected. Studies of Di Pietro et al. [40] and Hung and Liao [41] failed to demonstrate any significant differences in any long-term neurodevelopmental outcome measure between children with prenatal CPC detection and those without.
CONCLUSION FETAL ISOLATED VENTRICULOMEGALY Fetal isolated ventriculomegaly (atrial width 10 mm) is characterized by the absence of associated anomalies. Its prevalence is 0.39–0.87 births per 1000. In the systematic review and meta-analysis of Pagani et al. [34 ], the rate of chromosomal abnormalities was found to be 4.7%. Owing to the heterogeneity of the screening strategies and the populations studied, it is difficult to be certain regarding the incidence of chromosomal abnormalities in isolated mild ventriculomegaly. Nevertheless, given between mild ventriculomegaly and aneuploidies, it is likely that the risk will be high in the majority of cases regardless of a previous low-risk result. Ouahba et al. [35] provided criteria associated with an unfavorable outcome along with the associated anomalies. Goldstein et al. [36] advise that in the absence of associated malformations and aneuploidy, an isolated ventriculomegaly holds a favorable short-term neurodevelopmental outcome. However, follow-up sonograms and/or MRI in the third trimester or postnatally should be considered. &
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With the advances of FTS and rapid implementation of NIPT for screen-positive women in the first trimester of pregnancy, the prevalence of Down syndrome and other common aneuploidies will be decreasing. Although soft markers are of little value in population with normal FTS results, the generating of NCR and the search for the presence of two or more soft markers may improve detection rate in structurally normal fetuses. NIPT is a feasible option in such cases and it can replace invasive amniocentesis in many cases. Although the presence of specific soft markers requires pregnancy follow-up, parents may be reassured that association of soft markers with adverse pregnancy outcome in euploid (or presumably euploid) fetuses is rather weak with the majority of such fetuses having favorable long- term outcome. The future step in this controversial obstetrical issue was taken by Hurt et al. [42]. They have published a protocol on a large, prospective study designed to estimate the prevalence of soft markers in a population-based cohort of pregnant women and to investigate associations with adverse Volume 27 Number 2 April 2015
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Soft markers after normal first trimester screening Stefanovic
pregnancy outcomes. The study will also establish a cohort of children that can be followed-up to explore associations between specific markers and longer-term health and social outcomes. The utility of STUS for the screening of aneuploidies and fetal structural abnormalities will hardly be replaced in the near future. Furthermore, there is a hope that many forthcoming pregnancy complications could be detected as early as the 12th week of gestation expanding the variety of conditions that can be identified in early pregnancy with consequent improvement of the accuracy of the a priori risk based on maternal characteristics and medical history [43]. This might ultimately lead to the replacement of current ones (e.g. soft markers) and modify the value of others. Early identification of high-risk groups will also stimulate further research that will define the best protocol for their follow-up and development of strategies for the prevention and treatment of specific pregnancy disorders. Finally, parental anxiety associated with prenatal screening should be always be accompanied by a professional high-level counseling [44,45,46 ]. &&
Acknowledgements I would like to thank Ms Maaria Puupponen for her technical assistance. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Boyd PA, Chamberlain P, Hicks NR. 6-year experience of prenatal diagnosis in an unselected population in Oxford, UK. Lancet 1998; 14:1577–1581. 2. Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005; 353:2001– 2011. 3. Russo ML, Blakemore KJ. A historical and practical review of first trimester && aneuploidy screening. Semin Fetal Neonatal Med 2014; 19:183–187. This is a comprehensive and detailed review of first trimester aneuploidy screening. For patients at high risk for fetal aneuploidy, cell-free fetal DNA in maternal plasma has been incorporated as another screening test. FTS has other applications such as confirmation of dating of a pregnancy, establishment of chorionicity in multiple gestations and screening for congenital heart defects, skeletal dysplasias or other congenital malformation and conditions by increased nuchal translucency. 4. Bromley B, Shipp TD, Lyons J, et al. Detection of fetal structural anomalies in a basic first-trimester screening program for aneuploidy. J Ultrasound Med 2014; 33:1737–1745. 5. Agathokleous M, Chaveeva P, Poon LCY, et al. Meta-analysis of second&& trimester markers for trisomy 21. Ultrasound Obstet Gynecol 2013; 41:247– 261. This meta-analysis showed that the presence of sonographic markers increases, and absence of such markers decreases, the risk for trisomy 21. In the case of most isolated markers, there is only a small effect on modifying the pretest odds for trisomy 21, but with ventriculomegaly, nuchal fold thickness and aberrant right subclavian artery, there is a three to four-fold increase in risk and with hypoplastic nasal bone a six to seven-fold increase.
6. Lau TK, Evans MI. Second-trimester sonographic soft markers: what can we learn from the experience of first-trimester nuchal translucency screening? Ultrasound Obstet Gynecol 2008; 32:123–125. 7. Norton ME. Follow-up of sonographically detected soft markers for fetal & aneuploidy. Semin Perinatol 2013; 37:365–369. This article reviewed the most common second trimester sonographic soft markers that have been associated with fetal aneuploidy and also discusses in details the association of these soft markers with nonaneuploidy related adverse pregnancy outcome. 8. Krantz DA, Hallahan TW, Macri VJ, et al. Genetic sonography after firsttrimester Down syndrome screening. Ultrasound Obstet Gynecol 2007; 29:666–670. 9. Sood M, Rochelson B, Krantz D, et al. Are second-trimester minor sonographic markers for Down syndrome useful in patients who have undergone firsttrimester combined screening? Am J Obstet Gynecol 2010; 203:408e1– 408e4. 10. Aagaard-Tillery KM, Malone FD, Nyberg DA, et al., First and Second Trimester Evaluation of Risk Research Consortium. Role of second-trimester genetic sonography after Down syndrome screening. Obstet Gynecol 2009; 114:1189–1196. 11. Kaijomaa M, Ulander V-M, Ryynanen M, Stefanovic V. The significance of the & second trimester sonographic soft markers in pregnancies after normal first trimester screening. Prenat Diagn 2013; 33:804–806. The authors conclude that combination of any soft markers have very limited or no value in screening for Down syndrome in singleton pregnancies after normal FTS. 12. Breathnach FM, Malone FD, Lambert-Messerlian G, et al. First- and secondtrimester screening: detection of aneuploidies other than Down syndrome. Obstet Gynecol 2007; 110:651–657. 13. Paloma¨ki GE, Lee JE, Canick JA, et al. Technical standards and guidelines: prenatal screening for Down syndrome that includes first-trimester biochemistry and/or ultrasound measurements. Genet Med 2009; 11:669– 681. 14. Wax JR, Pinette MG, Cartin A, Blackstone J. Second-trimester genetic sonography after first-trimester combined screening for trisomy 21. J Ultrasound Med 2009; 28:321–325. 15. Bromley B, Shipp TD, Lyons J, et al. What is the importance of second& trimester ‘‘soft markers’’ for trisomy 21 after an 11- to 14-week aneuploidy screening scan? J Ultrasound Med 2014; 33:1747–1752. The authors conclude that second-trimester soft markers, especially a thickened nuchal fold, remain important observations in the detection of trisomy 21 by sonography among fetuses who have had first trimester sonographic screening for aneuploidy. 16. Tabor A, Madsen M, Obel E, et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986; 1:1287–1293. 17. Tabor A, Vestergaard CHF, Lidegaard O. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound Obstet Gynecol 2009; 34:14–19. 18. Buchanan A, Sachs A, Toler T, Tsipis J. NIPT: current utilization and implica&& tions for the future of prenatal genetic counseling. Prenat Diagn 2014; 34:850–857. This publication displays results of online survey of genetic counselors about the incorporation of NIPT into clinical practice in the context of genetic counseling and addresses concerns for obtaining proper informed consent. 19. Benn P, Cuckle H, Pergament E. Noninvasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol 2013; 42:15–33. 20. Badenas C, Rodrı´guez-Revenga L, Morales C, et al. Assessment of QF-PCR as the first approach in prenatal diagnosis. J Mol Diagn 2010; 12:828–834. 21. Stefanovic V, A¨yra¨s O, Eronen M, et al. Clinical utility of nuchal translucency & screening. Res Rep Neonatol 2014; 4:169–176. This is a comprehensive review article on the clinical utility of nuchal translucency screening regarding aneuploidies, fetal structural anomalies and single-gene disorders. The authors conclude that regardless of arising of new methods for aneuploidy screening, first trimester ultrasound screening is an extremely powerful tool of modern obstetrics and will remain for a long time. 22. Sonek J, Croom C. Second trimester ultrasound markers of fetal aneuploidy. && Clin Obstet Gynecol 2014; 57:159–181. The majority of this review deals with findings on a STUS and how they apply to screening for aneuploidy. However, to use them properly in risk calculation, it is critical to have an understanding of how they were developed, their limitations and general principles governing their use. 23. Hasson J, Wolman I. Is there still a use for sonographic fetal evaluation in the & era of widespread noninvasive prenatal tests? (Editorial). Research and Reports in Focused Ultrasound 2013; 1:1–2. The authors highlight the importance of the fetal ultrasound and conclude that it may be too early to abandon ultrasonographic fetal evaluation as a powerful screening tool in the era of widespread noninvasive prenatal tests. 24. Van den Hof MC, Wilson RD; Diagnostic Imaging Committee; Society of Obstetricians and Gynaecologists of Canada; Genetics Committee. Fetal soft markers in obstetric ultrasound. J Obstet Gynecol Can 2005; 27:592– 612. 25. Goetzinger KR, Cahill AG, Macones GA, Odibo AO. Echogenic bowel on second-trimester ultrasonography: evaluating the risk of adverse pregnancy outcome. Obstet Gynecol 2011; 117:1341–1348.
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Prenatal diagnosis 26. De Oronzo MA. Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome? J Prenatal Med 2011; 5:9–13. 27. Patel Y, Boyd PA, Chamberlain P, Lakhoo K. Follow-up of children with isolated fetal echogenic bowel with particular reference to bowel-related symptoms. Prenat Diagn 2004; 24:35–37. 28. Todros T, Massarenti I, Gaglioti P, et al. Fetal short femur length in the second trimester and the outcome of pregnancy. BJOG 2004; 111: 83–85. 29. Mathiesen JM, Aksglaede L, Skibsted L, et al., Danish Fetal Medicine Study && Group. Outcome of fetuses with short femur length detected at secondtrimester anomaly scan: a national survey. Ultrasound Obstet Gynecol 2014; 44:160–165. The results of Danish national survey study showed that SF at the secondtrimester anomaly scan is associated with a significantly higher relative risk of chromosomal abnormalities, and a substantially higher absolute risk for smallfor-gestational age infants and early preterm delivery. 30. Goetzinger KR, Cahill AG, Macones GA, Odibo AO. Isolated short femur length on mid-trimester ultrasound: a marker for fetal growth restriction and other adverse perinatal outcomes. J Ultrasound Med 2012; 31:1935–1941. 31. Rodriguez R, Herrero B, Bartha JL. The continuing enigma of the fetal & echogenic intracardiac focus in prenatal ultrasound. Curr Opin Obstet Gynecol 2013; 25:145–151. This is a comprehensive review on EIF as a soft marker. According to the available literature, as an isolated finding, its association with aneuploidy is low and in euploid fetuses, the presence of EIF is not an indication for prenatal or postnatal evaluation of fetal cardiac function. The management of fetuses with diffuse or multiple calcifications needs further research. 32. Odibo AO, Raab E, Elovitz M, et al. Prenatal mild pyelectasis: evaluating the thresholds of renal pelvic diameter associated with normal postnatal renal function. J Ultrasound Med 2004; 23:513–517. 33. John U, Ka¨hler C, Schulz S, et al. The impact of fetal renal pelvic diameter on postnatal outcome. Prenat Diagn 2004; 24:591–595. 34. Pagani G, Thilaganathan B, Prefumo B. Neurodevelopmental outcome in & isolated mild fetal ventriculomegaly: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2014; 44:254–260. According to the results of this review and meta-analysis, confirmed mild isolated ventriculomegaly is related to a prevalence of neurodevelopmental delay of 7.9%. However, the latter is similar to that reported in the general population and the published studies on ventriculomegaly do not allow accurate assessment of the severity of neurodevelopmental delay. Large cohort studies investigating the prevalence of childhood disability, instead of subtle neurodevelopmental delay, are required in children with isolated ventriculomegaly.
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35. Ouahba J, Luton D, Vuillard E, et al. Prenatal isolated mild ventriculomegaly: outcome in 167 cases. BJOG 2006; 113:1072–1079. 36. Goldstein I, Copel JA, Makhoul IR. Mild cerebral ventriculomegaly in fetuses: characteristics and outcome. Fetal Diagn Ther 2005; 20:281–284. 37. Voskamp BJ, Fleurke-Rozema H, Oude-Rengerink K, et al. Relationship of && isolated single umbiligal artery to fetal growth, aneuploidy and perinatal mortality: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2013; 42:622–628. A meta-analysis from three cohort studies and four case–control studies reporting on 928 pregnancies with iSUA found no statistically significant evidence that fetuses with iSUA have an increased risk of aneuploidy. Fetuses with an apparently isolated SUA potentially have an increased risk of impaired fetal growth and perinatal mortality. However, even in meta-analysis, the results were not statistically significant. The presence of SUA at second trimester screening sonogram requires meticulous fetal anatomy assessment, but as isolated finding the follow-up is not justified. 38. Chetty-John S, Zhang J, Chen Z, et al. Long-term physical and neurologic development in newborn infants with isolated single umbilical artery. Am J Obstet Gynecol 2010; 203:368e1–368e7. 39. Cheng PJ, Shaw SW, Soong YK. Association of fetal choroid plexus cysts with trisomy 18 in a population previously screened by nuchal translucency thickness measurement. J Soc Gynecol Investig 2006; 13:280–284. 40. DiPietro JA, Cristofalo EA, Voegtline KM, Crino J. Isolated prenatal choroid plexus cysts do not affect child development. Prenat Diagn 2011; 31:745–749. 41. Hung KL, Liao HT. Neonatal choroid plexus cysts and early childhood developmental outcome. J Formos Med Assoc 2002; 101:43–47. 42. Hurt L, Wright M, Brook F, et al. The Welsh study of mothers and babies: protocol for a population-based cohort study to investigate the clinical significance of defined ultrasound findings of uncertain significance. BMC Pregnancy Childbirth 2014; 14:164. (1–7). 43. Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther 2011; 29:183–196. 44. Viaux-Savelon S, Dommergues M, Rosenblum O, et al. Prenatal ultrasound screening: false positive soft markers may alter maternal representations and mother-infant interaction. PLoS One 2012; 7:e30395; DOI: 10.1371/journal. pone.003093. 45. Davies V, Gledhill J, McFadyen A, et al. Psychological outcome in women undergoing termination of pregnancy for ultrasound-detected fetal anomaly in the first and second trimesters: a pilot study. Ultrasound Obstet Gynecol 2005; 25:389–392. 46. Oepkes D, Yaron Y, Kozlowski P, et al. Counseling for noninvasive prenatal && testing (NIPT): what pregnant women may want to know. Ultrasound Obstet Gynecol 2014; 44:1–5. The authors stress the importance of counseling in the emerging era of NIPT.
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Soft markers for aneuploidy following reassuring first trimester screening: what should be done? Vedran Stefanovic
Purpose of review The present article aims to review the current role of the soft markers on the second trimester ultrasound (STUS) in women after reassuring first trimester screening (FTS) in singleton pregnancies. Recent findings Improvements in the FTS and the recent implementation of noninvasive prenatal testing (NIPT) for common aneuploidies have important impact on the prevalence of these conditions in the STUS. Some studies suggest that soft markers in the second trimester of the fetus without structural anomalies have a minor or no role in Down syndrome detection in a prescreened population with reassuring results. However, NIPT could be offered as a next step in the management of such pregnancies if the calculated new composite risk (NCR) for aneuploidy is increased. In the case of reassuring results, pregnancy follow-up for certain markers is advised. Summary NIPT has emerged as a new method of prenatal testing and is feasible in the second trimester in women with increased NCR. However, apart from the Down syndrome screening, STUS screening remains a powerful tool in screening for other fetal aneuploidies, structural anomalies and pathological placental conditions and detection of specific soft markers that require pregnancy follow-up. Keywords aneuploidy, counseling, noninvasive prenatal testing, screening, soft markers
INTRODUCTION Ultrasonography for aneuploidies and fetal structural anomaly screening in the second trimester of pregnancy (STUS) during week 18–20 was introduced into clinical practice almost 3 decades ago. A number of sonographic findings, known as soft markers, are often found in aneuploid fetuses (mostly in Down syndrome) and those with structural anomalies, although they are usually found as normal variants in a substantial proportion of euploid fetuses without structural anomalies. Despite the benefits of STUS, false-positive findings indisputably cause parental anxiety and amniocentesis for fetal cytogenetics is usually offered. The study of Boyd et al. [1] has assessed the effect of the detection of ultrasonographic soft markers on the efficacy of prenatal screening programmes reporting that for a 4% increase in the detection rate of congenital abnormalities (from 51 to 55%), there was a 12-fold increase in false-positives leading to the decrease in the specificity of STUS. Based on this report, concerns about the resource implications, risk of procedure-related normal pregnancy
losses and the short and long-term psychological sequelae arose. The list of soft markers has been going through extensive changes in recent years, with certain new markers added, whereas some have virtually disappeared. The commonly studied soft markers of aneuploidy include a thickened nuchal fold, short long bones (SLBs), mild fetal pyelectasis, echogenic intracardiac focus (EIF), absent or hypoplastic nasal bone and hyperechogenic bowels. Additionally, some researchers consider fetal venticulomegaly as an anomaly, and others include it in the list of soft markers. Finally, isolated single umbilical artery
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Corresponding to Vedran Stefanovic, A/Professor of Obstetrics, Gynecology and Fetomaternal Medicine, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 2, PL 140, 00029 HUS Helsinki, Finland. Tel: +358 50 427 1230; e-mail: vedran. [email protected] Curr Opin Obstet Gynecol 2015, 27:151–158 DOI:10.1097/GCO.0000000000000157
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KEY POINTS Soft markers at the STUS after reassuring FTS have limited value, but their presence may increase slightly the detection rate of Down syndrome. NIPT may be a feasible management option for women with NCR at STUS after presence of any soft marker or those with any combination of two soft markers. Soft markers in structurally normal euploid (or presumably euploid) fetuses have weak association with adverse pregnancy outcome. Pregnancy follow-up for specific soft markers is required, but the pregnancy outcome and the long-term outcome of such pregnancies are generally favorable. Despite widespread implementation of NIPT, ultrasound screening in the first and second trimester will remain the powerful obstetrical tool for screening of aneuploidies, structural abnormalities and pregnancy complications.
(iSUA) and choroid plexus cyst (CPC) are still attracting attention on the STUS, although they are not considered any more as soft markers. Screening for Down syndrome and other aneuploidies has been shifted from the second to the first trimester [2]. Before the introduction of noninvasive prenatal testing (NIPT), the most accurate screening test was first trimester combined screening (FTS), which is a combination of maternal age, fetal nuchal translucency and serum biochemistry achieving detection rate of 90% and 5% false-positive rate (FPR) [3 ]. FTS has provided ability for not only early detection of aneuploidies, but also severe congenital anomalies [4] and enabled early and safer pregnancy termination, if required. Recently published meta-analysis of the screening performance of the soft markers for trisomy 21 that included 48 studies concluded that their presence increased, and their absence decreased the risk for trisomy 21 [5 ]. As soft markers were introduced in obstetrical practice as promising markers for aneuploidy (almost exclusively for Down syndrome) in highrisk population and were not properly validated [6], there have been efforts for clarification of their significance after normal FTS. Additionally, the literature concerning need for follow-up of pregnancies with certain euploid fetuses is rather confusing [7 ]. The present article aims not only to review recent literature about the current role of the soft markers on the STUS in women after reassuring FTS, but to propose a simplified flow-chart for the &&
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management of such pregnancies (Fig. 1). Additionally, a summary of the pregnancy follow-up for specific soft markers is provided (Table 1).
STUDIES ON THE UTILITY OF SECOND TRIMESTER SCREENING AFTER FIRST TRIMESTER SCREENING Owing to the limited space, only few relevant studies will be included in this chapter. Although the results of some studies suggest that carefully performed STUS may improve the overall detection rate of Down syndrome after normal result on FTS, the others failed to confirm this. The simulation study of Krantz et al. [8] showed that by using individual marker likelihood ratios to modify the FTS for screen-negative patients, STUS detected an additional 6.1% of Down syndrome cases for an additional 1.2% FPR, giving a total detection rate of 94.6% and a total FPR of 5.4%. The retrospective cohort study of Sood et al. [9] included 3845 singleton pregnancies from the general population that underwent FTS followed by a STUS. Previously published likelihood ratios were used to modify each patient’s quantitative risk as ascertained by the FTS to generate a new composite risk (NCR). A fixed risk cut-off of 1/300 for Down syndrome was used for both FTS and the NCR. The principal finding of the study was that the use of soft markers may increase the positive predictive value in patients with high-risk FTS. The authors suggest that this group (particularly in the absence of major structural malformations) may benefit from the further risk adjustment at the STUS and avoid straightforward amniocentesis. On the contrary, in patients with a low risk on the FTS, the presence of soft markers did not have additional value in improving the detection rate of Down syndrome. A previously published study by Aagaard-Tillery et al. [10], which included 59 Down syndrome fetuses from 7842 pregnancies, showed an improvement in detection rate of the FTS from 88 to 95% on the STUS. The main limitation of this study is that it did not include short humerus, which has higher positive likelihood ratio than short femur (SF) (4.81 vs. 3.72). The study of Kaijomaa et al. [11 ] included 228 singleton pregnancies from the general obstetric population referred for two or more soft markers present at STUS in structurally normal fetuses with normal FTS (cutoff 1/250). Only two fetuses (0.9%) had significant aneuploidy: a case of trisomy 18 and triploidy case, respectively. There were two additional cases of chromosomal abnormalities: one case of 4% Down syndrome mosaicism (healthy euploid newborn) and clinically irrelevant case of &
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Soft markers after normal first trimester screening Stefanovic
Normal FTS*
Any SM on STUS Two or more SMs on STUS NCR generation
Increased NCR
NIPT
Normal NCR
Abnormal or no-call
Normal
Amniocentesis
Abnormal
Follow up specific SMs** *Cutoff should be determined by each expert institution ** See Table 1. FTS, first trimester screening; NCR, new composite risk; NIPT, noninvasive prenatal testing; SM, soft marker; STUS, second trimester ultrasound screening.
FIGURE 1. Proposal for the management of soft markers on second trimester ultrasound after reassuring first trimester screening.
chromosome 10 inversion with the healthy newborn, as well. Authors conclude that combination of any soft markers has very limited or no value in screening for Down syndrome in singleton pregnancies after normal FTS. However, this study did not use NCR nor the nuchal fold as a SF, which is known to have considerably high positive likelihood ratio of 23.30. The presence of three other chromosomal abnormalities than Down syndrome is in line with the results of Breathnach et al. [12] on the screening performance for detection of aneuploidies other than Down syndrome. That study used cutoff level of 1/300 for Down syndrome and 1/100 for trisomy 18. It is known that detection rate and associated FPR vary not only by screening cutoff level chosen, but also by the age distribution of the women tested, the gestational age at sampling and the
combination of markers chosen. Reports should give numerical risk, not just a screen-positive or screen-negative interpretation [13]. The study of Wax et al. [14] showed that application of STUS may lead to a very high screenpositive rate without improving the detection rate for Down syndrome. However, in this study, STUS was not performed as a universal screen on the entire population. The retrospective study of Bromley et al. [15 ] concluded that second trimester soft markers, particularly nuchal fold, are important findings in the detection of Down syndrome among fetuses who had FTS for aneuploidy. Among 42 fetuses with Down syndrome (0.4% of the cohort), there were nine fetuses who were first suspected of having aneuploidy based on the presence of soft markers without structural anomalies at STUS. Only three of
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Prenatal diagnosis Table 1. Proposal for pregnancy follow-up of specific soft markers Positive likelihood && ratio isolated [5 ]
Marker
Prenatal follow-up
Remarks
Prenatal ultrasound follow-up of fetal growth at 32 weeks of gestation, special attention to signs of gastrointestinal obstruction
Screening for perinatal infections (especially CMV) and cystic fibrosis according to the individually estimated risk
Prenatal ultrasound follow-up for fetal growth on the individual basis, screening for PIH, FGR and preeclampsia
Careful prenatal rule out of certain skeletal dysplasias (e.g. achondroplasia cases have normal femur length until >25 weeks of gestation)
Hyperechogenic bowel
11.44
Short femur length and humerus length
3.72 and 4.81
Echogenic intracardiac focus
5.83
Not justified
Diffuse myocardial calcifications with specific disease and poor outcome not considered as soft marker
Fetal pyelectasis APD 4–10 mm
3.72
Prenatal follow-up at 32 weeks of gestation, if renal pelvis >7 mm, postnatal follow-up suggesteda
Postnatal cystography and other individual urologic diagnostic procedures if renal pelvis >15 mm
Ventriculomegaly
27.52
Third-level prenatal sonography for other neural and extraneural anomalies, adjunct MRI
Prenatal screening for alloimmune thrombocytopenia and prenatal infections (especially CMV). Postnatal MRI and followup should continue until development is established as normal
Isolated single umbilical artery
N/A
Not justified
Not 21-trisomy soft marker, but one of the most frequently found anomalies at time of second trimester screening. Prenatal ultrasound follow-up for fetal growth
Choroid plexus cyst
N/A
Not justified
Not 21-trisomy soft marker, but screened still in many institutions. Postnatal evaluation not indicated, since normal long-term neurodevelopmental outcome has been addressed in cases of isolated choroid plexus (discovered both prenatally and in postnatal period)
APD, anterioposterior diameter; CMV, cytomegalovirus; FGR, fetal growth restriction; PIH, pregnancy-induced hypertension. a Optionally, if renal pelvis initially 7 mm, postnatal evaluation would be more appropriate than prenatal follow-up.
them underwent combined FTS (the rest had serial sequential test), of which had normal result on the combined FTS thus being detected on the basis of soft markers. Although aforementioned studies were very different in design and with different cutoff, it seems that in pregnancies with normal or borderline result in FTS, detection of soft markers on STUS may improve detection rate of Down syndrome and some other chromosomal abnormalities in the fetuses without structural anomalies.
PREGNANCY MANAGEMENT OPTIONS AFTER DETECTION OF SOFT MARKERS AND NORMAL FIRST TRIMESTER SCREENING The ultimate goal of noninvasive screening methods is to achieve acceptable high detection rate of aneuploidies with lowest possible false-positive results avoiding invasive procedures. 154
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Women should be informed that the risk of procedure-related miscarriage following amniocentesis at a mean gestational age of 16 weeks is around 1% [16]. The large Danish cohort study of more than 60 000 singleton pregnancies showed that the postprocedural fetal loss rates after CVS or amniocentesis before 24 completed weeks’ gestation were 1.4 and 1.9%, respectively, and total fetal loss rates were 2.0 and 2.3%, respectively. The fetal loss rate figures in this study consisted of a procedure-related loss rate plus the spontaneous miscarriage rate [17]. An increasing number of studies in high-risk pregnancies reported that NIPT analysis of maternal plasma can detect more than 99% of pregnancies with fetal trisomy 21 at FPR of less than 1%, with somewhat lower performance for trisomies 18 and 13 [18 ]. The implementation of this new and rather expensive technology into routine care is complex, as the information obtained from NIPT screening may overlap or contradict that from other &&
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methods of screening such as FTS or STUS. So far, there are no studies on the implementation of NIPT in women with normal FTS and soft markers detected on the second trimester screening. The acceptable concept would be to offer NIPT to two groups of women: those having increased NCR on the second trimester screening after normal FTS (excluding structural anomalies) or to women with combination of any two soft markers at the STUS (Fig. 1). On the contrary, cutoff level for the FTS should be determined by each specialized institution and all relevant soft markers should be included in the STUS screening. Although this approach would probably have a high uptake by women with such pregnancies because of its noninvasive nature, some worrisome issues arise. Reported failure rates of NIPT vary considerably and may be up to 5% [19]. After a failed result, NIPT can be repeated, which certainly adds additional time, costs and considerable parental anxiety to the screening and diagnostic process. Women who would consider a termination of pregnancy in case of a fetus with aneuploidy should always be counseled to have amniocentesis to confirm a positive NIPT result. In many countries, pregnancy termination for fetal indication is only possible up to 24 weeks’ gestation, so the time limit is an important issue. Fortunately, rapid PCR methods for the most common aneuploidies are available and further karyotyping would find out the very small number of cases with abnormal karyotype with clinical importance [20]. Obstetrical ultrasound in the first trimester has diagnostic and screening purpose, but despite NIPT screening for common aneuploidies, the role of first trimester ultrasound and STUS will hardly be replaced in the near future. Implementation of NIPT will have substantial impact on the prevalence of aneuploidies and the screening performance of STUS, although searching for fetal structural anomalies, single-gene disorders and placental abnormalities will probably never be replaced, both in euploid pregnancies with increased nuchal translucency at the time of FTS [21 ] and those with soft markers after normal FTS or already confirmed euploid pregnancy [22 ]. STUS evaluation thus remains the accessible, cost-effective and important examination for most pregnant women in the world, especially for those in low resource setting without logistical or financial possibility of having NIPT and invasive procedures. In such conditions, it is too early to abandon ultrasonographic fetal evaluation as a powerful screening tool [23 ]. &
&&
&
DO ISOLATED SOFT MARKERS REQUIRE PREGNANCY FOLLOW-UP? Although some soft markers have no significance beyond the association with aneuploidy, a few of them have potential nonaneuploidy-related associations with the pregnancy outcome [7 ]. The next chapter will briefly discuss this issue and propose a simplified guideline for specific soft markers (Table 1). Although CPC is not associated with Down syndrome and SUA has not been considered as a soft marker for a long time, they are frequently reported and are still on the soft marker list of certain national guidelines [24]. &
HYPERECHOGENIC BOWEL The prevalence of this subjective finding on the STUS ranges from 0.2 to 1.8%. Echogenic fetal bowel may be associated with congenital viral infections, aneuploidy, intra-amniotic bleeding or cystic fibrosis, anemia or FGR. Goetzinger et al. [25] reported that even after exclusion of cases with aneuploidy and cytomegalovirus (CMV) infection, echogenic fetal bowel on ultrasound was independently associated with an increased risk for both FGR and intrauterine fetal death (IUFD). The authors thus advocate serial fetal growth assessment. However, the review article of De Oronzo [26] stressed that a reproducible definition of echogenic fetal bowel is urgently needed so that large, controlled, prospective studies with standardized equipment settings and methods of collection could ultimately replace the largely retrospective data currently available. The study of Patel et al. [27] has provided reassurance that there was no evidence of any serious longterm bowel disease associated with isolated fetal echogenic bowel.
FEMUR LENGTH AND INTRAUTERINE FETAL GROWTH RESTRICTION Fetal SLBs at the time of STUS have been associated with aneuploidy, skeletal dysplasias, fetal structural anomalies, preeclampsia, IUFD and fetal growth restriction (FGR). In the study of Todros et al. [28], 50% of the women developed preeclampsia while undergoing follow-up for SF (femur length) and FGR. A recently published Danish study, which assessed the relationship between the finding of SF at STUS and pregnancy outcome, reported that SF was associated with a significantly higher relative risk of aneuploidies, small-for-gestational age infants and early preterm delivery [29 ]. The results of Goetzinger et al. [30] are in line with the previous one. Serial growth assessment may be warranted in these cases.
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ECHOGENIC INTRACARDIAC FOCUS
SINGLE UMBILICAL ARTERY
The presence of an EIF as a soft marker for fetal aneuploidy has been reported by many studies, particularly in high-risk populations. Postnatal cardiac function after the presence of prenatally diagnosed EIF has been evaluated in several studies showing no association with myocardial dysfunction during childhood. Additionally, electrocardiographic follow-up did not show any significant abnormalities irrespective of postnatal EIF persistence or resolution. The significance of isolated EIF is discussed in detail in the review article of Rodriguez et al. [31 ].
The reported incidence of SUA varies from 0.5% after the routine postnatal examination to 5.9% in a selected high-risk population. SUA appears to be an isolated finding (iSUA) in 56% of cases. Voskamp et al. [37 ] performed a meta-analysis on the significance of iSUA in 928 pregnancies, which did not show a statistically significant difference in aneuploidy rate, birth weight and incidence of FGR between iSUA fetuses and three vessel cord fetuses. Authors concluded that targeted growth assessment after diagnosis of iSUA should not be routine practice. Additionally, the large study of Chetty-John et al. [38] failed to demonstrate any clinically significant effect of iSUA with regard to growth or neurodevelopment (follow-up 7 years).
&
FETAL PYELECTASIS Fetal pyelectasis is defined as an anteroposterior measurement in a transverse scanning plane of 4 mm or larger in the second and/or 7 mm or larger in the third trimester, whereas pelvic anteroposterior diameter (APD) 10 mm or larger is criteria for hydronephorosis. Although fetal pyelectasis is usually self-limited, in some cases it can occur as true renal disease and may be associated with other fetal anomalies. There is a consensus that in the absence of other findings, isolated fetal pyelectasis is not a justification for karyotyping. The study of Odibo et al. [32] reported that the renal threshold that best predicted normal postnatal outcome was an APD of less than 7.0 mm after 32 weeks, yielding high sensitivity and specificity. John et al. [33] concluded that the dilatations of an APD larger than 4 mm, with spontaneous resolution at the post 33-week scan, need no further unnecessary postnatal investigations.
&&
CHOROID PLEXUS CYST CPC may be single or multiple and is identified in approximately 1 to 2% of fetuses in the second trimester usually as an isolated finding in otherwise normal low-risk pregnancy. The great majority of CPCs resolve by 28 weeks. CPC is not considered a structural nor functional brain abnormality. Cheng et al. [39] concluded that in pregnancies with isolated CPCs, fetal karyotyping is not indicated when no additional anomaly is detected. Studies of Di Pietro et al. [40] and Hung and Liao [41] failed to demonstrate any significant differences in any long-term neurodevelopmental outcome measure between children with prenatal CPC detection and those without.
CONCLUSION FETAL ISOLATED VENTRICULOMEGALY Fetal isolated ventriculomegaly (atrial width 10 mm) is characterized by the absence of associated anomalies. Its prevalence is 0.39–0.87 births per 1000. In the systematic review and meta-analysis of Pagani et al. [34 ], the rate of chromosomal abnormalities was found to be 4.7%. Owing to the heterogeneity of the screening strategies and the populations studied, it is difficult to be certain regarding the incidence of chromosomal abnormalities in isolated mild ventriculomegaly. Nevertheless, given between mild ventriculomegaly and aneuploidies, it is likely that the risk will be high in the majority of cases regardless of a previous low-risk result. Ouahba et al. [35] provided criteria associated with an unfavorable outcome along with the associated anomalies. Goldstein et al. [36] advise that in the absence of associated malformations and aneuploidy, an isolated ventriculomegaly holds a favorable short-term neurodevelopmental outcome. However, follow-up sonograms and/or MRI in the third trimester or postnatally should be considered. &
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With the advances of FTS and rapid implementation of NIPT for screen-positive women in the first trimester of pregnancy, the prevalence of Down syndrome and other common aneuploidies will be decreasing. Although soft markers are of little value in population with normal FTS results, the generating of NCR and the search for the presence of two or more soft markers may improve detection rate in structurally normal fetuses. NIPT is a feasible option in such cases and it can replace invasive amniocentesis in many cases. Although the presence of specific soft markers requires pregnancy follow-up, parents may be reassured that association of soft markers with adverse pregnancy outcome in euploid (or presumably euploid) fetuses is rather weak with the majority of such fetuses having favorable long- term outcome. The future step in this controversial obstetrical issue was taken by Hurt et al. [42]. They have published a protocol on a large, prospective study designed to estimate the prevalence of soft markers in a population-based cohort of pregnant women and to investigate associations with adverse Volume 27 Number 2 April 2015
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pregnancy outcomes. The study will also establish a cohort of children that can be followed-up to explore associations between specific markers and longer-term health and social outcomes. The utility of STUS for the screening of aneuploidies and fetal structural abnormalities will hardly be replaced in the near future. Furthermore, there is a hope that many forthcoming pregnancy complications could be detected as early as the 12th week of gestation expanding the variety of conditions that can be identified in early pregnancy with consequent improvement of the accuracy of the a priori risk based on maternal characteristics and medical history [43]. This might ultimately lead to the replacement of current ones (e.g. soft markers) and modify the value of others. Early identification of high-risk groups will also stimulate further research that will define the best protocol for their follow-up and development of strategies for the prevention and treatment of specific pregnancy disorders. Finally, parental anxiety associated with prenatal screening should be always be accompanied by a professional high-level counseling [44,45,46 ]. &&
Acknowledgements I would like to thank Ms Maaria Puupponen for her technical assistance. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Boyd PA, Chamberlain P, Hicks NR. 6-year experience of prenatal diagnosis in an unselected population in Oxford, UK. Lancet 1998; 14:1577–1581. 2. Malone FD, Canick JA, Ball RH, et al. First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005; 353:2001– 2011. 3. Russo ML, Blakemore KJ. A historical and practical review of first trimester && aneuploidy screening. Semin Fetal Neonatal Med 2014; 19:183–187. This is a comprehensive and detailed review of first trimester aneuploidy screening. For patients at high risk for fetal aneuploidy, cell-free fetal DNA in maternal plasma has been incorporated as another screening test. FTS has other applications such as confirmation of dating of a pregnancy, establishment of chorionicity in multiple gestations and screening for congenital heart defects, skeletal dysplasias or other congenital malformation and conditions by increased nuchal translucency. 4. Bromley B, Shipp TD, Lyons J, et al. Detection of fetal structural anomalies in a basic first-trimester screening program for aneuploidy. J Ultrasound Med 2014; 33:1737–1745. 5. Agathokleous M, Chaveeva P, Poon LCY, et al. Meta-analysis of second&& trimester markers for trisomy 21. Ultrasound Obstet Gynecol 2013; 41:247– 261. This meta-analysis showed that the presence of sonographic markers increases, and absence of such markers decreases, the risk for trisomy 21. In the case of most isolated markers, there is only a small effect on modifying the pretest odds for trisomy 21, but with ventriculomegaly, nuchal fold thickness and aberrant right subclavian artery, there is a three to four-fold increase in risk and with hypoplastic nasal bone a six to seven-fold increase.
6. Lau TK, Evans MI. Second-trimester sonographic soft markers: what can we learn from the experience of first-trimester nuchal translucency screening? Ultrasound Obstet Gynecol 2008; 32:123–125. 7. Norton ME. Follow-up of sonographically detected soft markers for fetal & aneuploidy. Semin Perinatol 2013; 37:365–369. This article reviewed the most common second trimester sonographic soft markers that have been associated with fetal aneuploidy and also discusses in details the association of these soft markers with nonaneuploidy related adverse pregnancy outcome. 8. Krantz DA, Hallahan TW, Macri VJ, et al. Genetic sonography after firsttrimester Down syndrome screening. Ultrasound Obstet Gynecol 2007; 29:666–670. 9. Sood M, Rochelson B, Krantz D, et al. Are second-trimester minor sonographic markers for Down syndrome useful in patients who have undergone firsttrimester combined screening? Am J Obstet Gynecol 2010; 203:408e1– 408e4. 10. Aagaard-Tillery KM, Malone FD, Nyberg DA, et al., First and Second Trimester Evaluation of Risk Research Consortium. Role of second-trimester genetic sonography after Down syndrome screening. Obstet Gynecol 2009; 114:1189–1196. 11. Kaijomaa M, Ulander V-M, Ryynanen M, Stefanovic V. The significance of the & second trimester sonographic soft markers in pregnancies after normal first trimester screening. Prenat Diagn 2013; 33:804–806. The authors conclude that combination of any soft markers have very limited or no value in screening for Down syndrome in singleton pregnancies after normal FTS. 12. Breathnach FM, Malone FD, Lambert-Messerlian G, et al. First- and secondtrimester screening: detection of aneuploidies other than Down syndrome. Obstet Gynecol 2007; 110:651–657. 13. Paloma¨ki GE, Lee JE, Canick JA, et al. Technical standards and guidelines: prenatal screening for Down syndrome that includes first-trimester biochemistry and/or ultrasound measurements. Genet Med 2009; 11:669– 681. 14. Wax JR, Pinette MG, Cartin A, Blackstone J. Second-trimester genetic sonography after first-trimester combined screening for trisomy 21. J Ultrasound Med 2009; 28:321–325. 15. Bromley B, Shipp TD, Lyons J, et al. What is the importance of second& trimester ‘‘soft markers’’ for trisomy 21 after an 11- to 14-week aneuploidy screening scan? J Ultrasound Med 2014; 33:1747–1752. The authors conclude that second-trimester soft markers, especially a thickened nuchal fold, remain important observations in the detection of trisomy 21 by sonography among fetuses who have had first trimester sonographic screening for aneuploidy. 16. Tabor A, Madsen M, Obel E, et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986; 1:1287–1293. 17. Tabor A, Vestergaard CHF, Lidegaard O. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound Obstet Gynecol 2009; 34:14–19. 18. Buchanan A, Sachs A, Toler T, Tsipis J. NIPT: current utilization and implica&& tions for the future of prenatal genetic counseling. Prenat Diagn 2014; 34:850–857. This publication displays results of online survey of genetic counselors about the incorporation of NIPT into clinical practice in the context of genetic counseling and addresses concerns for obtaining proper informed consent. 19. Benn P, Cuckle H, Pergament E. Noninvasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol 2013; 42:15–33. 20. Badenas C, Rodrı´guez-Revenga L, Morales C, et al. Assessment of QF-PCR as the first approach in prenatal diagnosis. J Mol Diagn 2010; 12:828–834. 21. Stefanovic V, A¨yra¨s O, Eronen M, et al. Clinical utility of nuchal translucency & screening. Res Rep Neonatol 2014; 4:169–176. This is a comprehensive review article on the clinical utility of nuchal translucency screening regarding aneuploidies, fetal structural anomalies and single-gene disorders. The authors conclude that regardless of arising of new methods for aneuploidy screening, first trimester ultrasound screening is an extremely powerful tool of modern obstetrics and will remain for a long time. 22. Sonek J, Croom C. Second trimester ultrasound markers of fetal aneuploidy. && Clin Obstet Gynecol 2014; 57:159–181. The majority of this review deals with findings on a STUS and how they apply to screening for aneuploidy. However, to use them properly in risk calculation, it is critical to have an understanding of how they were developed, their limitations and general principles governing their use. 23. Hasson J, Wolman I. Is there still a use for sonographic fetal evaluation in the & era of widespread noninvasive prenatal tests? (Editorial). Research and Reports in Focused Ultrasound 2013; 1:1–2. The authors highlight the importance of the fetal ultrasound and conclude that it may be too early to abandon ultrasonographic fetal evaluation as a powerful screening tool in the era of widespread noninvasive prenatal tests. 24. Van den Hof MC, Wilson RD; Diagnostic Imaging Committee; Society of Obstetricians and Gynaecologists of Canada; Genetics Committee. Fetal soft markers in obstetric ultrasound. J Obstet Gynecol Can 2005; 27:592– 612. 25. Goetzinger KR, Cahill AG, Macones GA, Odibo AO. Echogenic bowel on second-trimester ultrasonography: evaluating the risk of adverse pregnancy outcome. Obstet Gynecol 2011; 117:1341–1348.
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Prenatal diagnosis 26. De Oronzo MA. Hyperechogenic fetal bowel: an ultrasonographic marker for adverse fetal and neonatal outcome? J Prenatal Med 2011; 5:9–13. 27. Patel Y, Boyd PA, Chamberlain P, Lakhoo K. Follow-up of children with isolated fetal echogenic bowel with particular reference to bowel-related symptoms. Prenat Diagn 2004; 24:35–37. 28. Todros T, Massarenti I, Gaglioti P, et al. Fetal short femur length in the second trimester and the outcome of pregnancy. BJOG 2004; 111: 83–85. 29. Mathiesen JM, Aksglaede L, Skibsted L, et al., Danish Fetal Medicine Study && Group. Outcome of fetuses with short femur length detected at secondtrimester anomaly scan: a national survey. Ultrasound Obstet Gynecol 2014; 44:160–165. The results of Danish national survey study showed that SF at the secondtrimester anomaly scan is associated with a significantly higher relative risk of chromosomal abnormalities, and a substantially higher absolute risk for smallfor-gestational age infants and early preterm delivery. 30. Goetzinger KR, Cahill AG, Macones GA, Odibo AO. Isolated short femur length on mid-trimester ultrasound: a marker for fetal growth restriction and other adverse perinatal outcomes. J Ultrasound Med 2012; 31:1935–1941. 31. Rodriguez R, Herrero B, Bartha JL. The continuing enigma of the fetal & echogenic intracardiac focus in prenatal ultrasound. Curr Opin Obstet Gynecol 2013; 25:145–151. This is a comprehensive review on EIF as a soft marker. According to the available literature, as an isolated finding, its association with aneuploidy is low and in euploid fetuses, the presence of EIF is not an indication for prenatal or postnatal evaluation of fetal cardiac function. The management of fetuses with diffuse or multiple calcifications needs further research. 32. Odibo AO, Raab E, Elovitz M, et al. Prenatal mild pyelectasis: evaluating the thresholds of renal pelvic diameter associated with normal postnatal renal function. J Ultrasound Med 2004; 23:513–517. 33. John U, Ka¨hler C, Schulz S, et al. The impact of fetal renal pelvic diameter on postnatal outcome. Prenat Diagn 2004; 24:591–595. 34. Pagani G, Thilaganathan B, Prefumo B. Neurodevelopmental outcome in & isolated mild fetal ventriculomegaly: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2014; 44:254–260. According to the results of this review and meta-analysis, confirmed mild isolated ventriculomegaly is related to a prevalence of neurodevelopmental delay of 7.9%. However, the latter is similar to that reported in the general population and the published studies on ventriculomegaly do not allow accurate assessment of the severity of neurodevelopmental delay. Large cohort studies investigating the prevalence of childhood disability, instead of subtle neurodevelopmental delay, are required in children with isolated ventriculomegaly.
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35. Ouahba J, Luton D, Vuillard E, et al. Prenatal isolated mild ventriculomegaly: outcome in 167 cases. BJOG 2006; 113:1072–1079. 36. Goldstein I, Copel JA, Makhoul IR. Mild cerebral ventriculomegaly in fetuses: characteristics and outcome. Fetal Diagn Ther 2005; 20:281–284. 37. Voskamp BJ, Fleurke-Rozema H, Oude-Rengerink K, et al. Relationship of && isolated single umbiligal artery to fetal growth, aneuploidy and perinatal mortality: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2013; 42:622–628. A meta-analysis from three cohort studies and four case–control studies reporting on 928 pregnancies with iSUA found no statistically significant evidence that fetuses with iSUA have an increased risk of aneuploidy. Fetuses with an apparently isolated SUA potentially have an increased risk of impaired fetal growth and perinatal mortality. However, even in meta-analysis, the results were not statistically significant. The presence of SUA at second trimester screening sonogram requires meticulous fetal anatomy assessment, but as isolated finding the follow-up is not justified. 38. Chetty-John S, Zhang J, Chen Z, et al. Long-term physical and neurologic development in newborn infants with isolated single umbilical artery. Am J Obstet Gynecol 2010; 203:368e1–368e7. 39. Cheng PJ, Shaw SW, Soong YK. Association of fetal choroid plexus cysts with trisomy 18 in a population previously screened by nuchal translucency thickness measurement. J Soc Gynecol Investig 2006; 13:280–284. 40. DiPietro JA, Cristofalo EA, Voegtline KM, Crino J. Isolated prenatal choroid plexus cysts do not affect child development. Prenat Diagn 2011; 31:745–749. 41. Hung KL, Liao HT. Neonatal choroid plexus cysts and early childhood developmental outcome. J Formos Med Assoc 2002; 101:43–47. 42. Hurt L, Wright M, Brook F, et al. The Welsh study of mothers and babies: protocol for a population-based cohort study to investigate the clinical significance of defined ultrasound findings of uncertain significance. BMC Pregnancy Childbirth 2014; 14:164. (1–7). 43. Nicolaides KH. Turning the pyramid of prenatal care. Fetal Diagn Ther 2011; 29:183–196. 44. Viaux-Savelon S, Dommergues M, Rosenblum O, et al. Prenatal ultrasound screening: false positive soft markers may alter maternal representations and mother-infant interaction. PLoS One 2012; 7:e30395; DOI: 10.1371/journal. pone.003093. 45. Davies V, Gledhill J, McFadyen A, et al. Psychological outcome in women undergoing termination of pregnancy for ultrasound-detected fetal anomaly in the first and second trimesters: a pilot study. Ultrasound Obstet Gynecol 2005; 25:389–392. 46. Oepkes D, Yaron Y, Kozlowski P, et al. Counseling for noninvasive prenatal && testing (NIPT): what pregnant women may want to know. Ultrasound Obstet Gynecol 2014; 44:1–5. The authors stress the importance of counseling in the emerging era of NIPT.
Volume 27 Number 2 April 2015
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