The document discusses antenatal screening tests in the first and second trimesters. In the first trimester, screening includes ultrasound markers like nuchal translucency, nasal bone, ductus venosus Doppler, and biochemical markers like PAPP-A and beta-hCG. Combined first trimester screening using these markers can detect around 85-90% of Down syndrome cases at a 5% false positive rate. In the second trimester, screening includes a genetic sonogram and biochemical markers, with a detection rate of around 82% for Down syndrome. The document provides details on measuring and interpreting various first trimester ultrasound markers and their association with chromosomal abnormalities.

1. ANTENATAL SCREENING IN FIRST
AND SECOND TRIMESTER
Candidate : Dr Rajnish
Guide : Dr Vatsla Dadhwal
Sr-guide : Dr Shankar

2. TO BE DISCUSSED
First trimester screening
a)Ultrasound
b)Biochemical markers
Second trimester screening
a)Genetic sonogram
b)Biochemical markers

3. INTRODUCTION
What is a screening test?
 Assign risk estimate to individuals within a population.
 Unable to identify with certainty whether an individual is affected.
Why screening?
 Identifies high risk group.
 Reduces the new born incidence of major structural, single gene and
chromosomal disorders .
 Decrease the number of invasive procedures.
 Decrease parental anxiety.
 Early planning.

4. Criteria for Effective Screening
 Condition is frequent and serious enough to justify expense of screening.
 Availability of rapid, economical laboratory or physical test.
 Highly sensitive.
 Reasonably specific.
 Balances false positive rate (FPR) vs. detection rate (DR).
 Infrastructure in place for follow-up information, diagnostic testing,
genetic counseling, and treatment

5. Preliminary counseling before
prenatal screening:
 Prenatal screening starts from before conception:-
Preconceptional Genetic Counselling
 Risk to the fetus (affected)
 Consequences of the disease
 Risk and limitations of the screening
 Time required for reporting
 Need for an invasive procedure for definite diagnosis

6. PRECONCEPTION GENETIC COUNSELLING:
 Indications :-
 Previous pregnancy history
 Fetal demise
 Previous child with a genetic disorder
 Recurrent pregnancy loss
 Disorder
 Chromosomal: Down syndrome
 Structural: dwarfism, neural tube defect
 Metabolic disorder
 Hematological: anemia, bleeding disorder
 Mental retardation
 Family history of a genetic disorder
 Bleeding disorders: hemophilia
 Neurological disease: muscular dystrophy
 Mental retardation: fragile (X) syndrome

7. PRECONCEPTION GENETIC COUNSELLING (contd…)
 Ethnic origin from population at high risk of genetic disorder
 Ashkenazi Jewish: Tay-Sachs disease
 French-Canadian: Tay-Sachs disease
 African-American: Sickle cell anemia
 Mediterranean: Beta thalassemia
 Oriental: Alpha thalassemia and beta thalassemia
 Maternal medical disorder
 Diabetes
 Phenylketonuria
 Maternal medications
 Anticonvulsants
 Lithium
 Socially used drugs
 Alcohol ,cocaine COG-2008

8. Women with Increased Risk of
Fetal Aneuploidy
1. Singleton pregnancy and maternal age older than 35 at
delivery
2. Dizygotic twin pregnancy and maternal age older than
31 at delivery
3. Previous autosomal trisomy birth
4. Previous 47,XXX or 47,XXY birth
5. Patient or partner is carrier of chromosome
translocation
6. Patient or partner is carrier of chromosomal inversion
7. History of triploidy
8. Some cases of repetitive early pregnancy losses
9. Patient or partner has aneuploidy
10. Major fetal structural defect by sonography

9. 1st TRIMESTER SCREENING
 USG
− NT (Nuchal Translucency)
− NB (Nasal bone)
− DV (Ductus Venous)
− TR (Tricuspid Regurgitation)
− FMA (Frontomaxillary Angle)
− Intracranial translucency
− Structural anomalies
 Biochemical
− Dual marker
a) Free BHCG
b) PAPP-A

10. Maternal Serum Screening
• Photograph of Brahms Kryptor Immunoassay analyzer.

11. Normal anatomy
Screening for fetal defects
at 11-13+6 wks

12. NT
Nasal bone
Nasal tip
Diencephalon
Palate
The mid-sagital view of the fetal
face @ 11-13+6

13. NUCHAL TRANSLUCENCY:
 A lucent zone in back of
neck & the overlying skin.
 Between 11-13 wks/CRL
4.5-8.4mm.
 Usual cut off
3mm,although depending
upon period of gestation.
 Median at CRL4.5mm-
1.2mm & CRL 84mm-
1.9mm.
Snijders et al,Lancet-2000

14. NT Measurement Sonographic Criteria
(Fetal Medicine Foundation, UK)
 TA / TV approach on sonographer’s discretion, based on maternal body habitus, gestational age, fetal
position
 Gestation age limited to
 10- 14 weeks (CRL 36 – 80mm)
 Fetus examined - mid-sagittal
plane, neck neutral position
 Fetal image to occupy at least
 75% of the viewable screen
 Await movement to distinguish
amnion /overlying fetal skin
 Calipers on inner borders of
n.fold, perpendicular to fetal axis
 At least three NT measurements obtained, mean value used
 At least 20 minutes dedicated before abandoning as failed.

15. Increased NT > 95th centile at 11-14
Karyotype/CVS
Early detailed scan
Echocardiography
Genetic counseling
Abnormal Normal
20 week scan
Nuchal edema
> 5 mm
US at 16 weeks
Normal
Abnormal
Normal
Follow-up
Prenat Diagn 2002

16. ASSOCIATION OF NT WITH
TRISOMY:
 Fetal Medicine Foundation in England:
 total no patients-96,127
 detection rate:82%
 FPR-8% (Snijders et al,Lancet-1998)
 SURUSS Trial:
 detection rate-85%
 FPR-21%
 FASTER Trial: -
 detection rate-86%
 FPR-20% ( Malone F,N Eng J Med-2005)

17. Increased NT, Normal Karyotype
and Major Heart Defects
NT N CHD
3 mm 1102 5 /
1,000
4 mm 188 27 /
1,000
5 mm 56 54 /
1,000
>6 mm 43 233 /
1,000
Total 1,389 17 /
1,000
3mm 4mm 5mm >6mm
Lancet-2006

18. Nuchal Translucency
0
20
40
60
80
100
1 2 3 4 5 6 7 8
Nuchal translucency thickness (mm)
Abnormal
karyotype
(%)
Chromosomal Defects

19. 46.2%
>6.5 mm
24.2%
5.5-6.4 mm
18.5%
4.5-5.4 mm
10.0%
3.5-4.4 mm
2.5%
95th-99th centiles
1.6%
<95th centile
Major
defects
Nuchal
translucency
Normal karyotype

20. 11Fetal -14
wks
karyotyping
Anomaly scan
Chromosomal defects
Major abnormalities
Normal karyotype
No abnormalities
14-16 wks
Anomaly scan
Echocardiography
No abnormalities
Resolving nuchal
Major abnormalities
No abnormalities
Persistent nuchal
Infection screen
Genetic testing
20 wks
Anomaly scan
Echocardiography
No abnormalities
Major abnormalities
No abnormalities
Persistent nuchal
Infection screen
Genetic testing
Management of increased nuchal
translucency
Lancet-2006

21.  Nasal bone hypoplasia
 62% trisomy 21, 57% tris 13, 67% tris 18,1% of normal fetuses
 angle of insonation of fetal nose - 45 to 135 to avoid false shortening.
 2 echogenic lines - superficial nasal skin, deeper – nasal bone,
echolucent at distal end (Cicero et al, Usg Obstet Gynecol 2003)
 No relationship between presence/absence NB with biochem. Tests
(Spencer, Nicolaides; Prenat Diagn, 2005)

22. HOW TO MEASURE NASAL
BONE?
 Fetus should face
transducer.
 Face & thorax
occupy whole image.
 Angle of insonation-
90`.
 Presence of equal(=)
sign.
 If bottom part of
equal sign is
missing-absent
nasal bone.
NT
Nasal bone
Nasal tip
Diencephalon
Palate
Sonek et al , AJOG-2006

23. ABSENT Nasal Bone
 The investigators reported the nasal bone to be absent in 73 percent
of Down syndrome fetuses, but in only 0.5 percent of karyotypically
normal fetuses.
 In the FASTER—trial of more than 6300 women of average risk, no
case of Down syndrome detected by nasal bone assessment.
 Nasal bone sonography is more difficult to accomplish than nuchal
translucency.
 Poor screening tool in the general population.
Malone and colleagues (2005)
 The Maternal Fetal Medicine Nuchal Translucency Oversight
Committee recently recommended that nasal bone assessment
should be used only as a secondary or contingency marker in
screening protocols
(Rosen and associates, 2007).
.

24. Ductus venosus Doppler @ 11-
13+6 wks:
 Discriminate between chromosomally normal & abnormal fetus.
 Determine which non aneuploid fetus with increased NT are at increased
risk of cardiac defect.
 Aneuploid fetus-90% flow is absent/reversed during atrial contraction.
(Matias et al,Ultrasound Obstet Gynecol 2003 )

25. Reversed flow in the Ductus venosus @ 11-13+6 wks
Gate: 0.5-1 mm
Low filter: 50 Hz
Sweep speed: 2cm/s
Contamination from hepatic vein
Contamination from umbilical vein
Trisomy 21
n=125
65%
Normal
n=21,000
3.5%
(Ultrasound Obstet Gynecol 2003)

26. Frontomaxillary angle and fetal
aneuploidy
 The normal ranges of the frontomaxillary angle measurements
decrease with advancing gestational age.
Ultrasound Obstet Gynecol 2007
 They are independent of NT measurement, presence or absence of
the nasal bone, and maternal serum biochemistries.
AM J Obstet Gynecol 2007
 Shallow FMF angles are seen in trisomy 21,18,13.
 Fetuses with trisomies 21, 18,13 have FMF angle measurements
that are above the 95th percentile in 45%, 58% ,48% cases.
Ultrasound Obstet Gynecol 2007
 In a study, 782 euploid fetuses and 108 fetuses with trisomy 21, a
92% detection rate for a 3% false positive rate was achieved by
adding FMF angle measurement to the combined screen.
Ultrasound Obstet Gynecol 2008

27. How to measure Frontomaxillary angle
 CRL 45-84 mm 11 to 13 + 6 wk.
 MID saggital fetus must be facing toward the transducer.
 Face of the transducer is approximately
parallel to long axis of the nasal bone.
 Fetal profile must include an echogenic
line representing the skin over nasal
bridge and in front of it an echogenic
line representing the skin over the
nasal tip.
 Intracranial structures hypoechoic areas
representing the region of the thalamus,
pons and medulla oblangata.
 Space between the upper palate and the
nose should be devoid of an echogenic
structure representing the zygomatic
process.
 FMF angle first ray is drawn along the upper
age of the hard palate, apex of the angle is
at the anterior age of the maxillar second
ray runs upward from the apex resting on the
echogenic line behind the skin(the non-calcified
metopic suture)
 A) An acute angle in an euploid fetus.
 B) An obtuse angle in a fetus with trisomy 21

28. Tricuspid valve doppler and fetal aneuploidy
 The prevalence of tricuspid regurgitation varies with
gestational age and also increase as the NT
measurement increases.
 Tricuspid regurgitation is seen in trisomy 21,18,13 and
monosomy X.
 The prevalence of tricuspid regurgitation in fetuses with
trisomies 21, 18, 13 and monosomy X is 56%, 33%, 30%
and 38% respectively.
 The prevalence of tricuspid regurgitation in euploid
fetuses is 1%.
 In a study, 19 614 fetuses, a 96% detection rate for a 3%
false positive rate was achieved for trisomy 21 by adding
tricuspid valve evaluation to the combined screen.
 The detection rates for trisomies 18 ,13, and monosomy
X were 92%, 100% and 100% respectively.
Ultrasound Obstet Gynecol 2009

29.  Other fetal measurements potentially affected
in chromosomally abnormal fetuses in first
trimester USG scan
• Fetal heart rate.
• Maxillary length.
• Ear length.
• Femur length.
• Humeral length.

30. Free beta-hCG
Produced in the trophoblast cells.
Maternal serum concentration reaches a
peak at appr. 15 wks, followed by a rapid
decline until 17wks and more gradual
decrease between 17 and 22 wks.
Free beta-hCG are increased twice the
normal value during second trimester in
aneuploidy fetus.

31. PAPP-A (pregnancy associated
plasma protein- A)
 PAPP-A level normally increases with gestation.
 It is lower in pregnancies of trisomy 21.
 Used alone in the first trimester allows for
trisomy 21 DR 40% and FR 5%.
 Increase PAPP-A level in women were
associated with high risk of
preeclampsia,preterm birth.
Hypertens Pregnancy 2003

32. First Trimester Screening:
Markers Detection Rate
PAPP-A, hCG 60%
PAPP-A, free beta-hCG 66%
PAPP-A, h-hCG 67%
NT, PAPP-A, hCG 82%
NT, PAPP-A, free beta-hCG 83%
NT, PAPP-A, h-hCG 84%
At 5% FPR.
Health Technol Assess-2003

33. First Trimester Combined
 One stage test NT and serum
 IT is Performed First trimester 11.0-13.6 wk
 Dating Method CRL only.
 Components NT, PAPP-A, hCG.
 Test performance
− DR 85%-90%
− FPR 4%-6%
− PPV 1 in 40
 Risk cut-offs for
− Down Syndrome ≥ 1 in 230 in first trimester.
− Trisomy 18 ≥ 1 in 100 in second trimester
− NTDs Not screened
 Comments
− Earlier screening
− Performance comparable to serum integrated
− Requires NT
− Does not screen for NTDs
− CVS for diagnosis COG 2008

34. Combined First Trimester Screening: Detection
Rates for 5% False Positive Rate
 STUDY PATIENTS DS CASES DETECTION RATE(%)
 BUN 8256 61 79%
 FASTER 38,167 117 85%
 SURUSS 47,053 101 83%
 Nicolaides 75,821 325 90%
 TOTAL 169,257 604 87%
(Malone FD et al , N Eng J Med 2005) (Wald et al , Health Technol Assess 2003)
(Nicolaides et al,Ultrasound Obstet Gynecol 2005) (Wapner et al , N Eng J Med 2003)

35. 2nd TRIMESTER SCREENING
 TRIPLE SCREEN
a) UE3
b) B-HCG
c) MS-AFP
 QUADRUPLE TEST
− Triple screen markers +DIA
 PENTA SCREEN
− Quadruple test + h-HCG

36. Obstet Gynecol-2008
Quad Screen
 Includes
 Maternal age
 AFP
 hCG
 Uncongugated estriol (E3)
 Dimeric inhibin A (DIA)
 Improves DS detection rate 79% with 5% FPR

37. Penta Screen
 Includes
 Maternal age
 AFP
 hCG
 uE3
 DIA
 h-hCG
 Improves DS detection rate (83% with 5% FPR)
Human Gen-2008

38. Unconjugated estriol
 Estriol, steroid molecule synthesized from the
combined activity of the fetal adrenal gland and
the placenta.
 The precursor of estriol is
dehydroepiandrosterone.
 The concentration of estriol in the second
trimester of pregnancy is decreased about 25%
in aneuploid pregnancies.
 Very low level of uE3 are associated with Smith-
Lemli-Optiz syndrome, placental sulfatase
deficiency.

39. Alpha fetoprotein
 This glycoprotein is synthesized early in gestation by the
fetal yolk sac and later by the fetal gastrointestinal tract
and liver.
 Its concentration increases steadily in both fetal serum
and amnionic fluid until 13 weeks, after which, levels
rapidly decrease.
 AFP is found in steadily increasing quantities in maternal
serum after 12 weeks.
 In NTDs and ventral wall defects, permit AFP to leak into
the amnionic fluid, resulting in maternal serum AFP
levels that may be dramatically increased.
 Several factors effects levels of MS AFP- maternal wt,
gestational age, race, DM, multifetal gestation.

40. Prenat Diag-2000
Dimeric Inhibin A (DIA)
 Hormone synthesized by the gonads and placenta
 Levels vary the least with increasing gestational age in second trimester
 Elevated maternal serum levels associated with DS
 Increase levels in down syndrome about 1.77 MoMs
 The concentration of inhibin A is not used to calculate the risk for T18
 1996: addition to triple screen could improve DS detection rate
 Quad screen proposed
 Test at 15-20 weeks gestation

41. Prenat Diag-2008
Hyperglycosylated hCG (h-hCG):
 Produced very early in pregnancy by placenta
 Elevated levels associated with DS
 Low levels associated with trisomy 18, trisomy 13, triploidy, and
preeclampsia
 In 2000, h-hCG reported to add value to second trimester screening
 Penta screen proposed.

42. (BJOG-2007)
AFP, hCG, uE3, and DIA vs
Gestational Age:
15 20
Gestational Age (weeks)
AFP
UE3
HCG
Screening Window
DIA

43. Second Trimester Quad
 One stage test maternal serum only
 IT is Performed in Second Trimester 15.0-22.6 wk.
 Dating Method CRL or BPD Preferred. LMP accepted.
 Components AFP, uE3,hCG,DIA.
 Test performance
− DR 80%-85%
− FPR 5%-8%
− PPV 1 in 50
 Risk cut-offs for
− Down Syndrome ≥ 1 in 270 in Second trimester.
− Trisomy 18 ≥ 1 in 100 in Second trimester
− NTDs AFP ≥ 2.0 MoM.
 Comments
− Best second trimester screening test
− U/S not Required
− Screens for NTDs
− Amniocentesis for diagnosis COG 2008

44. Second trimester marker patterns
in common aneuploidies
Anomaly AFP HCG Inhibin A uE3
T21 Low High High Low
T18 Low Low Small
decrease
Low
T13 Small
increase
Normal Normal Normal
Turner Small
decrease
High/ low High/ low Small
decrease
Other sex
chromo abn
Normal or
high
Normal or
high
Triploidy High High
AJOG-2006

45. Health Technol Assess-2003
Second Trimester DS Screening
Markers Detection Rate
Age, AFP 42%
Age, AFP, hCG 67%
Age, AFP, hCG, uE3 72%
Age, AFP, hCG, uE3, DIA 79%
Age, AFP, hCG, uE3, DIA, h-
hCG
83%
At 5% FPR.

46. First trimester:
 NT, PAPP-A, hCG
Second trimester:
 Triple screen—MSAFP, hCG, uE3
 Quadruple screen—MSAFP, hCG, uE3, Inh-A
 Genetic sonogram—ultrasound markers
 Extended sonogram—serum+ ultrasound markers
Integrative (nondisclosure of first trimester results)
 Integrated (NT, PAPP-A, quad screen)
 Serum integrated (PAPP-A, quad screen)
Sequential (disclosure of first trimester results)
Independent: independent interpretation of first and second
trimester tests
DS Risk Assessment Approaches

47. DS Risk Assessment Approaches
 Step-wise
 *First trimester test
 Positive: diagnostic test offered
 Negative: second trimester test offered; final risk estimate
incorporates first and second trimester results
 Contingent
*First trimester test
 Positive: diagnostic test offered
 Negative: no further testing
 Intermediate: second trimester test offered; final risk estimate
incorporates first and second trimester results
Semin Perinat-2005

48. Serum Integrated
 Two stage test serum only
 IT is Performed in First and second trimester10.3-13.6+15.0-22.6wk
 Dating Method CRL or BPD preferred. LMP accepted.
 Components PAPP-A in first trimester. Quad markers in second
trimester
 Test performance
− DR 85%-90%
− FPR 4%-6%
− PPV 1 in 40
 Risk cut-offs for
– Down Syndrome ≥ 1 in 110 in second trimester.
– Trisomy 18 ≥ 1 in 100 in second trimester
− NTDs AFP ≥ 2.0 MoM
 Comments
– Fewer false positives than Quad
− NT not required
− Screens for NTDs
− Amniocentesis for diagnosis
− CVS for diagnosis COG 2008

49. Full Integrated
 Two stage test NT and Serum
 IT is Performed in First and second trimester 10.3-13.6+15.0-22.6wk
 Dating Method CRL only.
 Components NT and PAPP-A in first trimester Quad markers in
second trimester
 Test performance
− DR 85%-90%
− FPR 1%-2%
− PPV 1 in 10
 Risk cut-offs for
– Down Syndrome ≥ 1 in 110 in second trimester.
– Trisomy 18 ≥ 1 in 100 in second trimester
− NTDs AFP ≥ 2.0 MoM
 Comments
– Fewer false positives
− Safest test by far
− Requires NT
− Screens for NTDs
− Amniocentesis for diagnosis COG 2008

50. 1st trimester NT and PAPP-A
+ maternal age
2 trimester quad markers
(AFP, uE3, hCG, inhA)
Screen Positive.
Counseling on risks
and benefits of
amniocentesis
Risk
≥ 1 in 110 Risk
< 1 in 110
Screen Negative.
No further action
Integrated Test
COG 2008

51. Sequential Integrated
 Two stage test NT and Serum very high risks reported in first
trimester
 IT is Performed First and second trimester10.3-13.6+15.0-22.6wk
 Dating Method CRL only.
 Components NT and PAPP-A in first trimester. Quad markers in
second trimester
 Test performance
− DR 85%-90%
− FPR 1.5%-2.5%
− PPV 1 in 10
 Risk cut-offs for
– Down Syndrome ≥ 1 in 25 (first); ≥ 1 in 110 (second)
– Trisomy 18 ≥ 1 in 100 in second trimester
− NTDs AFP ≥ 2.0 MoM
 Comments
– Fewer false positives
− Requires NT
− Screens for NTDs in most
– First trimester diagnosis for some
– CVS/amniocentesis for diagnosis

52. 1st trimester NT and PAPP-A
+ maternal age
Screen Positive.
Counseling on risks
and benefits of early
prenatal diagnosis
(CVS).
Risk not reported.
Patient continues on
to 2 trimester stage
of Integrated Test
(quad markers
Screen Positive.
Counseling on risks
and benefits of
amniocentesis
Risk
≥ 1 in 110 Risk
< 1 in 110
Risk
≥ 1 in 25
Risk
< 1 in 25
Screen Negative.
No further action
Sequential Integrated Test
COG 2008

53. Screening Program Performance:
Markers FPR (%) DR (%)
NT 15-23 85
Combined test 4-5 85
Triple test 9-14 85
Quadruple test 6-7 85
Serum integrated test 4 85
Integrated test 2 85
Contingency test 0.9 or 5 85 or 94
Health Technol Assess-2003

54. Ultrasound

55. SCREENING BY USG
 USG screening categories of fetal defects
− Chromosomal, Malformations, Genetic syndromes, Dysplasias
 A marker for aneuploidy is a finding on USG which has a different
prevalence in the euploid population VS the aneuploid population.
 A likelihood ratio is based by dividing the two prevalences.
 Pure (“Soft”) markers
− Findings which in themselves are generally not clinically
significant but have an increased prevalence in the aneuploid
population.
− The prevalence tends to change with gestational age.
− Prevalence may be affected by ethinicity.
 Anomalies as markers
− Structural anomalies as markers are those findings which not
only have clinical significance but they also are associated with
an increased risk of chromosomal defects.
− Not all anomalies are markers for aneuploidy.
Fetal medicine foundation/USA

56. Continue…
 Modify the a priori risk of aneuploidy (maternal age, gestational age,
history, serum biochemistries, prior screening)
 The more markers are present in a single fetus, the more likely it is
that aneuploidy is present.
 The more anomalies are present in a fetus, the more likely it is that
aneuploidy is present.
 Most markers are either reported as present or absent.
 Even if a measurement is used, most markers are reported as either
yes or no rather than a continuum.
 Notable exceptions
− Nuchal translucency measurement (11-136/7 wks)
− Nasal bone measurement(2nd trimester only)
− Frontomaxillary facial angles(1st and 2nd trimesters)

57. Genetic sonogram
 Major anomalies
− Congenital heart defects
− Duodenal atresia
 Major markers
− Increased nuchal thickness
− Hyperechoic bowel
− Shortened humerus
− Shortened femur
− Echogenic intracardiac focus
− Renal Pyelectasis
 Minor markers
− Shortened or absent nasal bone
− Foot length
− ‘Sandal gap’ of the foot
− Widened ischial spine angle
− Hypoplasia of the mid-phalynx of the fifth digit
− Brachycephaly
Obstetric Evidence Based Guidelines 2007

58. Most Common Structural Defects Diagnosed
Prenatally during Screening at 11 to 14 Weeks
 Atrloventrlcular septal defects and
hypoplastic left heart syndrome
Acrania and alobar holoprosencephaly
Omphalocele and gastroschlsis
Megacystis
Lethal skeletal defects

59. MINOR SOFT MARKERS:

60. Ultrasound screening in T2 aneuploidy
markers of the genetic sonogram
 Structural anomalies including cardiac (4 chamber and outflow
tracts)
 Short femur (observed/expected< 10 percentile)
 Short humerus (observed/expected< 10 percentile)
 Pyelectasis (anteroposterior diameter of renal pelvis > 4 mm)
 Nuchal fold thickening (> 6 mm)
 Echogenic bowel similar echogenicity to iliac bones
 Choroid plexus cysts (> 10 mm)
 Hypoplastic middle phalanx of the fifth digit
 Wide space between first and second toes (sandle gap )
 Two vessel umbilical cord
 Echogenic intracardiac focus, short tibia, short fibula, short ear
(since October, 1997)
 Absent nasal bone (since 2003)
J Obstet Gynecol-2006

61. Detection Rate for a 5% False-Positive Rate
With Standard Screening Policies and With
Risk Modified by Genetic Sonogram Result
Policy Standard After Sonogram
Combined 81 90*
Quadruple 81 90
Integrated 93 98
Stepwise 97 98
Contingent 95 97
Stepwise sonogram — 90
Contingent sonogram — 90
ACOG 2009

62. Abnormalities in Trisomy 21
 Markers:
 Nuchal edema
 Absent/short nasal bone.
 Flat face (shallow FMF
angle).
 Hyperechoic bowel
 Short humerus
 Short femur
 Mild Ventriculomegaly.
 Clinodactyly.
 Sandal gap
 Echogenic foci
 Mild hydronephrosis.
 Major Defects:
Cardiac (septal) defects
Duodenal atresia

63. • Echogenic intracardiac
foci: occur in 5% of normal
pregnancies and in
approximately 13–18% of
Down’s syndrome gestations.
• This has been found by most
investigators not to be
significantly more frequent in
Down’s syndrome pregnancies
than in normals (low specificity).
• The risk does not seem to vary if
the focus is in right or left
ventricle or if it is unilateral or
bilateral, but may be affected by
ethnicity.
• calcified papillary muscle seen
as bright dot
Nicolaides KH, Snijders RJM, Sebire N (eds)
Obstetric Evidence Based Guidelines 2007

64. Pyelectasis
- AP diameter renal pelvis > 4 mm,15-20 wks
- 20-25% of fetuses with Down syndrome
- with a single or multiple additional USG markers :
8-fold and 62-fold increase in major trisomies
(Bornstein E.Am J Obstet Gynecol 2007)
 This has been found by some not to be
significantly more frequent in Down’s
syndrome pregnancies than in normals
(low specificity)
Nicolaides KH, Snijders RJM, Sebire N (eds)
Obstetric Evidence Based Guidelines 2007

65. Detection and False-Positive Rates of Screening
Test for Trisomy 21
SCREENING TEST DETECTION FALSE-POSITIVE
RATE (%) RATE (%)
MA 30 (or 50) 5 (or 15)
MA + serum β-hCG + PAPP-A at 60 5
11–14 wk
MA + fetal NT at 11–14 wk 75 (or 70) 5 (or 2)
MA + fetal NT + NB at 11–14 wk 90 5
MA + fetal NT + serum β-hCG + 90 (or 80) 5 (or 2)
PAPP-A at 11–14 wk
MA + fetal NT + NB + serum β-hCG + 97 (or 95) 5 (or 2)
PAPP-A at 11–14 wk
MA + serum biochemistry at 15–18 wk 60–70 5
Ultrasound for fetal defects and 75 10–15
markers at 16–23 wk
MA + serum β-hCG + PAPP-A at 90 2-3
11–14 wk ± DV, TR, NB (individual
risk-oriented two-stage)

66. Abnormalities in Trisomy 18
 Markers:
 Ventriculomegaly.
 Choroid plexus cysts
 Microgynathia.
 Nuchal oedema.
 Talipes
 Rocker bottom feet
 2 vessel cord
 IUGR
 Major Defects:
Strawberry shaped head
Posterior fossa cyst
Facial cleft
Cardiac defects
Diaphragmatic hernia
Omphalocoele
Renal anomalies
Radial anomalies
Clenched fists

67. Abnormalities in Trisomy 13
 Markers:
 Ventriculomegaly.
 Nuchal oedema.
 Echogenic foci
 Postaxial polydactyly
 IUGR
 Major Defects:
Holoprosencephaly
Microcephaly
Anophthalmia
Facial cleft
Cardiac defects
Renal anomalies
Omphalocoele
Myelomeningocele

68. Algorithm for clinical management
based on T2 ultrasound
Normal ultrasound
(no markers present)
1 isolated marker
(except nuchal fold)
>2 markers, OR thick
nuchal fold, OR
structural anomaly
Low risk*
High risk
Low risk *
High risk
Low risk *
High risk
No further testing
Down syndrome risk
adjustment
No further testing
Offer genetic
amniocentesis
Offer genetic amniocentesis
Offer genetic amniocentesis
Seminars in Perinatology, 2003

69. Risk assessment – isolated
markers
Background
risk
LR derived
from screening
test
Adjusted risk
=
X

70. Likelihood ratio of developing T21 for
different 2nd trimester USG marker
Markers LR for isolated marker
Nuchal fold 9.8
Short humerus 4.1
Short femur 1.6
Hydronephrosis 1.0
Echogenic focus 1.1
Echogenic bowel 3.0
Major defects 5.2
LR calculated by Nicolaides 2003 from two major series by Nyberg DA 2001
and Bromley B 2002 (AJOG-2004)

71. Incidence of chromosomal defects in
relation to number of sonographically
detected abnormalities:
Abnormalitie
s
N= Chromosomal
defects (%)
1 1128 2
2 490 11
3 220 32
4 115 52
5 53 66
6 40 63
7 16 69
8 24 92
(Nicolaides et al, Lancet 1992)

72. Genetic sonogram Nyberg scoring
index
Sonographic findings Points
Major anomalies 2
Nuchal fold ≥5mm 2
Short femur 1
Short humerus 1
Pylectasis ≥4mm 1
Hyperechogenic bowel 1
Echogenic intracardiac foci 1
Benacerraf BR, Neuberg D, Bromley B, et al: Sonographic scoring
index for prenatal detection of chromosomal abnormalities. J Ultrasound
Med 11:449-458, 1992

73. LR of isolated marker in Four large
studies:
Markers Smith-
Bindnam
JAMA 2001
FASTER Nyberg
1998
N=142
Bromley
2002
None NA NA 0.36 0.22
Nuchal fold 17 8.3 11 12
Bright
Bowel
6.1 4.6 6.7 NA
Short
humerus
7.5 NA 5.1 6
Short femur 2.7 4.4 1.5 1
EIF 2.8 1.8 1.8 1.2
Pyelectasis 1.9 NA 1.5 1.3

74. Indication Time
Anencephaly 10-12 weeks
Spina bifida 16-18 weeks
CVS 18-22 weeks
Limbs 16+ serial
Hydrocephalous, microcephaly 16+ serial
Renal 16+serial
Face and mouth 18-22
Ant abdominal wall 16-18
CALLEN’S USG BOOK
USG timing:

75. ACOG Guideline for Fetal
Aneuploidy Screening
Offer to all patients who present before 20
weeks of gestation
Maternal age alone should not be the only
screening criteria
Approaches using first and second
trimester tests are best
All patients should have the option of an
invasive (diagnostic) test
ACOG 2007

76. RCOG recommendation 2007
Pregnant women should be offered screening for Down’s syndrome with
a test which provides a detection rate above 75% and a false positive
rate of less than 3%.
Performance measures should be age standardised and based on a
cutoff of 1/250 at term.
The following tests currently meet this standard:
• From 11 to 14 weeks:
• the combined test (NT, hCG and PAPP-A)
• From 14 to 20 weeks:
• the quadruple test (hCG, AFP, uE3, inhibin A)
• From 11 to 14 weeks AND 14 to 20 weeks:
• the integrated test (NT, PAPP-A + hCG, AFP, uE3, inhibin A)
• the serum integrated test (PAPP-A + hCG, AFP, uE3, inhibin A).
Pregnant women should be given information about the detection rates
and false positive rates of any Down’s syndrome screening test being
offered and about further diagnostic tests that may be offered.
The woman’s right to accept or decline the test should be made clear.

77. Advantages of the 11-14 week
screening scan in multiple gestation
Identification of all multiple gestations
Determination of chorionicity
Evaluation of anatomy
Nuchal translucency screening is the best
screening tool for aneuploidy available.
Chorionicity in decision making
− Calculation of risks based on NT screening.

78. Assessing risk for trisomy 21 in
twins
 Monochorionic twins
 Measure NT in each fetus
 Calculate risks for each
fetus
 Counsel by the
AVERAGE risk
 Invasive technique: CVS
Dichorionic twins
 Measure NT in each fetus
Calculate risks for each fetus
Give risks for each fetus
Select invasive technique
depending on the risk level.

79. Assessing risk for trisomy 21in twins
Monozygotic:
− Risk one fetus has trisomy 21 = 1 in 200
− Risk both fetuses have trisomy 21 = 1 in 200
Dizygotic:
− Risk one fetus has trisomy 21 = 1 in 100
− Risk both fetuses have trisomy 21 = 1 in
40000

80. Twins: screening with biochemistry
Lower sensitivity
Not discriminative
If used in conjunction with NT,
biochemistries reduce the false positive
rate.