This document discusses various soft markers that can be detected on ultrasound during the second trimester to screen for fetal aneuploidies like Down syndrome. It describes markers like thickened nuchal fold, mild ventriculomegaly, echogenic bowel, mild pyelectasis, single umbilical artery, echogenic intracardiac focus, choroid plexus cysts, and enlarged cisterna magna. For each marker, it discusses the association with aneuploidy and provides recommendations from medical organizations on evaluation and need for further testing.

1. Second trimester soft markers of
aneuploidy
Dr.Omneya Nagy Elmakhzangy
Special Fetal care Unit
Ain Shams University

2. Antenatal soft ultrasound markers
• Are fetal sonographic findings that are
generally not abnormalities as such but are
indicative of an increased age adjusted risk of
an underlying fetal aneuploidic or some non
chromosomal abnormalities.
• Based on this definition the term “soft
markers” has been banned by some institutes
and the term “Anatomical variant” is used
instead.

3. Aneuploidy
• Is the presence of an abnormal number of
chromosomes in a cell.
• Most common aneuploidies screened for :
• Trisomy 21 (Down’s Syndrome) .
• Trisomy 13 (Patou’s Syndrome) .
• Trisomy 18 (Edward’s syndrome) .
• Monosomy X
• Triploidy

4. Available screening methods according
to gestational age
• At 11–14 weeks:
– nuchal translucency (NT)
– combined test (NT + hCG + PAPP-A)

5. • At 15 – 20 weeks:
– double test (hCG, uE3)
– triple test (hCG, uE3, AFP)
– quadruple test (hCG, uE3, AFP, inhibin A)

6. • At 11–14 weeks and then at 15–20 weeks:
– integrated test (combined test at 11–14
weeks, followed by AFP, uE3 and inhibin A at
15–20 weeks)
– serum integrated test (PAPP-A and hCG at
11–14 weeks, followed by AFP, uE3 and inhibin
A at 15–20 weeks).

7. Risk Numerical calculation
• The fetal medicine foundation Calculator:
https://fetalmedicine.org/research/assess/triso
mies
• Individual laboratory risk calculation reported
with the results.

8. Diagnostic Tests
• Invasive :
1-Chorionic villous sampling (CVS)
2-Amniocentesis
• Non-invasive : (non-invasive prenatal
test(NIPT)
cell-free fetal DNA test (cffDNA)

9. ACOG Guidelines for screening
• All women, regardless of age, should be
offered aneuploidy screening before 20 weeks'
gestation.
• Women seen during the second trimester are
limited to ultrasonography or quadruple
screening.
• Those seen in the first trimester can be
offered both first- and second-trimester
screening tests.

10. • When discussing options with patients,
physicians should provide information on
detection and false-positive rates, advantages
and disadvantages, limitations, and the risks
and benefits of each screening test and
diagnostic procedure so that the patient can
make an informed decision.
• A numeric risk assessment allows the patient
to determine the risk and consequences of
giving birth versus proceeding with diagnostic
testing.

11. Detection rates.
SCREENING TEST DETECTION RATE (%)
NT measurement 64-70
NT measurement, PAPP-A, free or total
beta-hCG
82-87
Triple screen (maternal serum alpha-
fetoprotein, hCG, unconjugated estriol)
69
Quadruple screen 81
Integrated (NT, PAPP-A, quadruple screen) 94-96
Serum integrated (PAPP-A, quadruple
screen)
85-88
Adapted with permission from ACOG Committee on Practice Bulletins. Screening for fetal
chromosomal abnormalities. Obstet Gynecol 2007;109:218.

12. AIUM 2014
• Historically, risk assessment was based on
second-trimester maternal serum screening
along with genetic sonography to identify
structural anomalies and “soft markers” for
aneuploidy.
• The question that remains is whether there is
any importance to a soft marker for
aneuploidy in the second trimester fetus with
normal anatomic survey results once a risk of
Down syndrome has been established in the
first trimester.

13. • 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.

14. NHS (National health service)
• Anatomical variants detected between 18-
20+6 weeks are considered here. Women who
are found to have a low chance of Down’s
syndrome following first or second trimester
screening, or who have declined screening,
should not be referred for further assessment
of chromosome abnormality even if the
variants below are detected, whether single
or multiple.

15. • The only variant that may indicate an
increased chance of aneuploidy is:
Nuchal fold greater than 6 mm.

16. Other markers to be considered
• Choroid plexus cyst
• Dilated cistern magna
• Echogenic focus in the cardiac
ventricle
• Single umbilical artery.

17. Findings have possible significance
other than possible aneuploidy
• Ventriculomegaly (atrium greater than 10
mm)
• Echogenic bowel (with density equivalent to
bone)
• Renal pelvis dilatation (AP measurement
greater than 7mm)
• Small measurements compared to dating
scan (significantly less than 5th centile on
national charts)

18. Society of Obstetricians and
Gynaecologists of Canada practice
Guidelines

19. THICKENED NUCHAL FOLD
• The nuchal fold is the skin thickness in the
posterior aspect of the fetal neck.
• A nuchal fold measurement is obtained in a
transverse section of the fetal head at the
level of the cavum septum pellucidum and
thalami, angled posteriorly to include the
cerebellum.

21. Values
• A measurement of 6 mm be considered
significant between 18 and 24 weeks and a
measurement of 5 mm be considered
significant at 16 to 18 weeks.

22. Important notes
• Thickened nuchal fold should be distinguished
from cystic hygroma, in which the skin in this
area has fluid-filled loculations.

23. • A thickened nuchal fold should not be
confused with nuchal translucency, which is a
specific measurement of fluid in the posterior
aspect of the neck at 11 to 14 weeks’
gestation.

24. Association With Fetal Aneuploidy
• The risk for Down syndrome increased by
approximately 17-fold

25. Recommendations
• A thickened nuchal fold significantly increases
the risk of fetal aneuploidy. Expert review is
recommended, and karyotyping should be
offered (II-1 A).
• A thickened nuchal fold is associated with
congenital heart disease and rarely with other
genetic syndromes. Expert review is
recommended (II-2 B).

26. MILD VENTRICULOMEGALY
• Defined as a lateral ventricular measurements
from 10 to 15 mm.
• The measurement should be in the true axial
plane at the atria of the lateral ventricle and
glomus of the choroid plexus.

28. Association With Fetal Aneuploidy
• When MVM is isolated, the incidence of
abnormal fetal karyotype is estimated at 3.8%
(0 to 28.6%).

29. Recommendations
• Cerebral ventricles greater than or equal to 10 mm are
associated with chromosomal and central nervous
system pathology.
• Expert review should be initiated to obtain the
following:
a. A detailed anatomic evaluation looking for
additional malformations or soft markers (III-B);
b. laboratory investigation for the presence of
congenital infection or fetal aneuploidy (III-B);
• Neonatal assessment and follow-up are important to
rule out associated abnormalities a).

30. ECHOGENIC BOWEL
• Echogenic bowel is defined as fetal bowel with
homogenous areas of echogenicity that are
equal to or greater than that of surrounding
bone.
• The echogenicity has been classified as either
focal or multifocal.

32. Association With Fetal Aneuploidy
• The presence of echogenic bowel is associated
with an increased risk for fetal aneuploidy,
including trisomy 13, 18, 21, and the sex
chromosomes.

33. Recommendations
• Grade 2 and 3 echogenic bowel is associated with
both chromosomal and nonchromosomal
abnormalities.
• Expert review is recommended to initiate the
following:
• a. detailed ultrasound evaluation looking for
additional structural anomalies or other soft
markers of aneuploidy (II-2 A);
• b.detailed evaluation of the fetal abdomen
looking for signs of bowel obstruction or
perforation (II-2 B);

34. • c. detailed evaluation of placental
characteristics (echogenicity, thickness,
position, and placental cord insertion site) (II-2
B);
• d. genetic counselling (II-2 A);
• e. laboratory investigations that should be
offered, including fetal karyotype, maternal
serum screening, DNA testing for cystic
fibrosis (if appropriate), and testing for
congenital infection (II-2 A).
• f. Growth monitoring (II-2 A)

35. MILD PYELECTASIS
• Mild pyelectasis is defined as a hypoechoic
spherical or elliptical space within the renal
pelvis that measures 5mm to 10 mm.
• The measurement is taken on a transverse
section through the fetal renal pelvis using the
maximum anterior-to-posterior measurement.

37. Association With Fetal Aneuploidy
• It is an isolated finding in fetal Down
syndrome in approximately 2%.
• In the absence of other risk factors, the
chance of Down syndrome in the presence of
isolated mild pyelectasis remains small and
does not justify an invasive diagnostic
procedure.

38. Recommendations
• All fetuses with renal pelvic measurements 5 mm
should have a neonatal ultrasound, and those
having measurements > 10 mm should be
considered for a third trimester scan for follow up
(II-2 A).
• Isolated mild pyelectasis does not require fetal
karyotyping (II-2 E).
• Referral for pyelectasis should be considered with
additional ultrasound findings and (or) in women
at increased risk for fetal aneuploidy owing to
maternal age or maternal serum screen results
(II-2 A).

39. SINGLE UMBILICAL ARTERY
• Single umbilical artery (SUA) is the absence of
one of the arteries surrounding the fetal
bladder and in the fetal umbilical cord.

42. Association With Fetal Aneuploidy
• Isolated SUA has not been found to be
significantly associated with fetal aneuploidy.
• Isolated SUA has been associated with both
underlying fetal renal and cardiac
abnormalities, as well as low birth weight

43. Recommendations
• The finding of a single umbilical artery
requires a more detailed review of fetal
anatomy, including kidneys and heart (fetal
echo) (II-2 B).
• An isolated single umbilical artery does not
not warrant invasive testing for fetal
aneuploidy (II-2 A).

44. ECHOGENIC INTRACARDIAC FOCUS
• Echogenic intracardiac focus (EICF) is defined
as a focus of echogenicity comparable to
bone, in the region of the papillary muscle in
either or both ventricles of the fetal heart.
• 88% percent are only in the left ventricle, 5%
are only in the right, and 7% are biventricular.

46. Recommendations
• Isolated EICF with a fetal aneuploidy risk less than
1/600 by maternal age (31 years) or maternal
serum screen requires no further investigations
(III-D).
• Women with an isolated EICF and a fetal
aneuploidy risk greater than 1/600 by maternal
age (31 years) or maternal serum screening
should be offered counselling regarding fetal
karyotyping
• Women with right-sided, biventricular, multiple,
particularly conspicuous, or nonisolated EICF
should be offered referral for expert review and
possible karyotyping (II-2 A).

47. CHOROID PLEXUS CYSTS
• Choroid plexus cysts (CPCs) are
sonographically discrete, small cysts (3mm)
found in the choroid plexus within the lateral
cerebral ventricles of the developing fetus at
14 to 24 weeks’ gestation.

49. Recommendations
• Isolated CPCs require no further investigation
when maternal age or the serum screen
equivalent is less than the risk of a 35-year-old (II-
2 E).
• Fetal karyotyping should only be offered if
isolated CPCs are found in women 35 years or
older or if the maternal serum screen is positive
for either trisomy 18 or 21 (II-2 A).
• All women with fetal CPCs and additional
malformation and soft markers should be offered
referral and karyotyping (II-2 A).

50. ENLARGED CISTERNA MAGNA
• The cisterna magna is measured on a transaxial
view of the fetal head angled 15 degrees caudal
to the canthomeatal line. The anterior/posterior
diameter is taken between the inferior/posterior
surface of the vemis of the cerebellum to the
inner surface of the cranium.
• An enlarged cisterna magna is defined by an
anterior/posterior diameter >10 mm
• The measurement will be falsely exaggerated by a
steep scan angle through the posterior fossa or
dolichocephaly

54. Recommendations
• An isolated enlarged cisterna magna is not an
indication for fetal karyotyping (III-D).
• With an enlarged cisterna magna, expert review
is recommended for follow-up ultrasounds and
possible other imaging modalities (for example,
MRI) and investigations(III-B).
• If the enlarged cisterna magna is seen in
association with other abnormal findings, fetal
karyotyping should be offered (III-B).

55. Rhizomelia

56. SHORT FEMUR LENGTH
• A short femur length is defined as a
measurement below the 2.5th percentile for
gestational age .
• The femur should be measured with the bone
perpendicular to the ultrasound beam and
with epiphyseal cartilages visible but not
included in the measurement.

58. Recommendations
• Relative femur shortening is an ultrasound
marker for trisomy 21 and should be
considered during tertiary level evaluation (II-
1 A).
• If a femur appears abnormal or measures
short on screening ultrasound, other long
bones should be assessed and referral with
follow-up ultrasound considered (III-B).

59. SHORT HUMERUS LENGTH
• A short humerus length is defined as a length
below the 2.5th percentile for gestational age

60. Recommendations
• Relative humeral shortening is an ultrasound
marker for trisomy 21 and should be
considered during tertiary level evaluation (II-
1 A).
• If the humerus is evaluated and appears
abnormal or short, other long bones should
be assessed and referral with follow-up
ultrasound considered (III-B).

61. NASAL BONE
• Absence of the nasal bone or measurements
below 2.5th percentile are considered
significant.
• The fetus is imaged facing the transducer with
the fetal face strictly in the midline

62. Association With Fetal Aneuploidy
• The likelihood ratio for this finding varies
depending on ethnic background.
• overall likelihood ratio for Down syndrome
was found to be 132 for Caucasians and 8.5
for African Caribbeans.

65. FIFTH FINGER CLINODACTYLY
• Fifth finger clinodactyly is defined by a
hypoplastic or absent mid-phalanx of the fifth
digit.

69. Association With Fetal Aneuploidy
• Fifth finger clinodactyly is found in 60% of
neonates affected with Down syndrome.
• During antenatal screening, it has been found
to be present in 3.4% of normal fetuses and in
18.8% of fetuses with Down syndrome.

70. Recommendations
• Imaging of the outstretched hand to evaluate
for fifth finger clinodactyly is not an
expectation during the 16- to 20-week
ultrasound (III-C).
• Fifth finger clinodactyly is associated with
trisomy 21 and should be considered for
research or tertiary-level evaluation (III-B).

71. SANDAL GAP
• Sandal gap is described as the separation of
the great and second toe and has been
reported to be present in 45% of newborns
with trisomy 21.1
• Prenatal diagnosis requires imaging the foot
and toes from the plantar view.