PRENATAL ANEUPLOIDY SCREENING –

STEPWISE APPROACH

DR BHARTI PANT GAHTORI

MATERNAL –FETAL MEDICINE SPECIALIST
 MAIN COMPONENT
BIRTH DEFECT – MARKING OUT ANEUPLOIDY

HISTORICAL PERSPECTIVE AND SCREENING TIMELINE

PRINICPLES OF SCREENING

FIRST AND SECOND TRIMESTER MARKERS

NIPT BASICS

BASIC INTERPRETATION & RISK STRATIFICATION

BASIC COUNSELLING AND FOLLOW UP

TAKE HOME MESSAGE FOR OBSTETRICIANS - WHAT THEY CAN’T AVOID


CONGENITAL
ANOMALIES
 Occurs during
morphogenesis
 Multifactorial influences
 Single to multiple
 Age not a factor
 Rarely mental
retardation
 Preventable with low
recurrence
 Good prognosis if mild
 CHD, NTD,Cleft palate
BIRTH DEFECTS
CHROMOSOMAL
SYNDROMES
 Mainly caused due to meiotic
non-dIsjunction,
 mosaicism & translocation
 Abnormality in number or
structure of chromosomes
 Age related
 Lethal,if alive associated with
mental disabilities
 1-5% reccurence rate
 Trisomies ,
turners ,kleinfelters,
polyploidy
GENETIC
DEFECT/SYNDROME
Single/multiple gene defect
Caused by mutations or
inherited
Follows Mendelian
inheritance and pedigree
charts
Related to race , sex ,
consanguinity , family
history
With or without structural
&mental disabilities
Noonans
syndrome ,Thalesssmia ,
 CHROMOSOMAL
ABNORMALITIES

NUMERICAL STRUCTURAL

ANEUPLOIDY
DELETION
Extra or missing CH(2n+1) POLYPLOIDY
DUPLICATION
TRISOMIES ( T21.18 &13) 3N ,4N , 5N
TRANSLOCATION
MONOSOMY TRIPLOIDY ,
INVERSION
( TURNERS) TETRAPLOIDY
AUTOSOME/SEX CH
 WHY DOWN SYNDROME IS IMPORTANT IN ANC

Birth defects - 3-6% of LB

Of them Chr abnormalities ~ 0.1-0.2% of LB
OTHER COMMON
95% all trisomies are trisomy 18, 13 and 21 ANEUPLOIDIES
Of them Downs syndrome ~ 1:650 live births
Most common identifiable cause of intellectual • Trisomy 18 ( Edwards)
• Other trisomies are low incidence T18 (1:3000) & T13
disability.
Quality of life issues with Long life span • Trisomy 13(Patau)
( 1:5000)
On USG – Non specific and subtle finding WITH only • Monosomy X
• Mainly
30% major fatalanomalies
detectable and reach max 1 year of infancy
• Major ( turners syndrome)
Though related toand specific
increasing ultrasound
maternal anomalies ( 90-95%)
age ( meiotic
disjunction) but 70% of affected mothers are young • Triploidy
detectable in utero.
( translocations) • Sex chr abnormalities
The extra chromosome rarely comes from the father.
XXY ( Kleinfelters ) &
Women with Down syndrome has 50% risk of DS baby
XXX
 TRISOMY 21( historical perspective)
• 1866 - British physician John Langdon Down
described it as flat profile , small nose and
redundant skin
• 1959 - French geneticist Jerome Lejeune
discovered the chromosome abnormality.
• 1961 - The Lancet letter to the editor
proposed the name Down's Syndrome.
• 1970 -Up to the mid-1970s amniocentesis
done blindly. First ultrasound guided
amniocentesis done in 1972 .
 DOWN SYNDROME SCREENING- TIMELINE

Introduction of Inhibin –
A 94% DR at
Quad test- 80-85% DR 2.5% FP
Combined test - 85-
90% DR
NT alone- 65-70% DR
• AFP – NTD -98% DR for DS
later DS T18 , T13
• AFP + Beta -Rh typing
HcG(50% DR) -Sex
• AFP + βHcG+ determination
uE3 (60%)
Amniocentesis
> 35 yrs
later CVS
CHROMOSOMAL ANOMALIES – WHY SCREEN ?

 Specific diagnosis of chromosomal anomaly is reached via – CVS OR

AMNIOCENTESIS – Karyotyping /QF –PCR /FISH / MICROARRAY etc
 Inherent risk of fetal loss – 1:200 to 1:800
 I in 200 applies that if all pregnancy had invasive procedure 1 normal fetus would be
lost for 4 cases of DOWNS babies IDEAL SCREENING
 Also due to high abortion risk in chromosomal anomalies 30% TEST
DIE before reaches
till term so over testing might happen
 Age > 35 yrs cannot be made a universal protocol
- 70% DS babies are born to young mothers
- With age at the time of conception increasing difficult to provide invasive to all
 HENCE A SIMPLE , NONINVASIVE , COSTEFFECTIVE AND RELIABLE
SCREENING TEST ALWAYS A PRIORITY
 SCREENING TEST
 Screening is a process of identifying apparently
healthy people who may be at increased risk of a
disease or condition
 Screening test identifies individual as broadly
-low risk
- High risk( proceed to Diagnostic procedures)
 Screening test differs from diagnostic tests
- It has False positives and False negatives

These tests do not diagnose a problem only: they only signal that
further testing needs to be done
 SCREENING- Important parameters
SENSITIVITY : Ability to detect SPECIFICITY : Ability to detect individuals
individuals with the presence of target who are completely disease free.
condition.

FALSE POSITIVE :Individuals not with FALSE NEGATIVE : Individuals who have
Aimtheisdisease
to have high detection
but detected with it. Leastrate
the with the but
the disease lowest false
detected free positive
of it. Least the
False Positive more the test sensitive false negative more the test specific

POSITIVE PREDICITIVE VALUE(PPV) : NEGATIVE PREDICTIVE VALUE (NPV)-is

is the probability that a subject with the post-test probability that the subject has
a positive (abnormal) test actually has no disease given a negative test result .
the disease.
 WHY EARLY THE SCREENING THE BETTER ??
 The most sensitive and specific ultrasound and serum
markers are between ( 11- 13wks +6d)
 Early risk stratification can be done
 If need of early diagnostic test – we have min15- 21 day with
us to get Karyotyping or microarray report
 If positive early termination is possible
 If report negative can rule out other causes and appropriate
management can be pursued
Hence try to clear all the tests before 20 weeks so that decision can be taken
by the parents regarding continuation or termination
PRENATAL SCREENING OPTIONS AGE
PAST H/O DS
BABY
 SERUM( BIOCHEMICAL) MARKERS Free β HcG,
PAPP-A, Inhibin • NT +NB ,
–A, uE3 , AFP • TR , DV,ARSA
 ULTRASOUND( PHENOTYPIC) • ANOMALY
NT + DUAL MARKERS
MARKERS TEST (Free β
 COMBINED SCREENING HcG, PAPP-
A) NIPS
RISK
 Cell free DNA BASED -NIPS ( GENOTYPIC STRATIFICATIO
N
MARKER
 OTHER OPTIONAL TESTS ( VALIDATED)- TO IMPROVE DETECTION RATE
COUNSELLING
 TRIPLE TEST ( 1ST TRIMESTER)
 SERUM INTEGRATED ( 1ST + 2ND )
 FULLY INTEGRATED ( 1ST + 2ND ) DIAGNOSTI
 SEQUENTIAL SCREENING ( 1ST ( convey risk if > 1:50) ) ELSE ADD 2ND T quad test C TEST
 GENETIC SONOGRAM ( MAJOR + SOFT MARKERS)
 PRETEST COUNSELLING FOR SCREENING TEST
- what all to tell?

 Screening is not diagnostic test

 Early the better
 What are you screening – only few chromosomal disorders not all
 If test is positive – need for confirmatory test arises
 Availability of – CVS/Amniocentesis - cost , minor procedure &
complication rate
 Risk of pregnancy loss ( 0.2- 1%. )
 No intrauterine treatment available for chromosomal
anomalies yet
FIRST TRIMESTER SCREENING : INVERTING THE PYRAMID OF
ANTENATAL CARE
 Fetal medicine established as a new
field
 Advancements in the resolution &
quality of ultrasound machines and
addition of new finer serum
markers with better sensitivity and
specificity
 Availability of specialised
laboratories in small cities with
special softwares generated to
calculate combined risk
 SCREENING at FIRST VISIT ( IF BETWEEN 6-10WKS)

Age > 35 yrs at EDB else less age ULTRASOUND (6-10WKS)
H/o downs baby/ delayed milestones Confirmation of an
Dizygotic twins with maternal; age > 31 yrs intrauterine live pregnancy
Race and ethnicity H/o consanguinity
 H/o Known teratogen exposure e.g drugs and Single or multiple
radiations or abortifacient intake
H/o High grade fever with rash , nonimmune to
Rubella – s/o viral infections
If multiple – confirmation of
H/o Exposure to medical conditions including chorionicity
maternal diabetes , Epilepsy, severe thyroid ds ,
autoimmune ds. Estimation and Correction of
H/o termination of pregnancy for fetal abnormality gestational age
H/o previous child born with multiple defects
H/o bleeding disorder in the baby Looking out for early feature of
Family h/o inheritable genetic disease increase NT or delayed growth
 COMPONENTS OF FIRST TRIMESTER SCREENING

COMBINING ULTRASOUND 2D+ 3D β HcG /free β HcG + PAPP-A

:
1 ) SCREENING FOR ANEUPLOIDY /CHROMOSOMAL
DEFECTS
2) SCREENING FOR FETAL STRUCTURAL ANOMALY
3) SCREENING FOR RISK OF EARLY PRECLAMPSIA & FGR

4) MULTIFETAL GESTATION SCREENING FOR

CHRIONICITY &
PREDICTION OF RELATED COMPLICATIONS
5) DETECTION AND SCREENING FOR GENETIC
DISORDERS
6) SCREENING FOR PRETERM LABOUR
 FIRST TRIMESTER ULTRASOUND MARKERS
NUCHAL
TRANSLUCENY
NASAL BONE

 DUCTUS VENOSUS

 TRICUSPID
REGURGITATION
 ABERRANT RT SUBCLAVIAN ARTERY
( ARSA)
 NUCHAL TRANSLUCENCY

• Dr Langdon Down observed thick

skin behind neck post natal

• Dr Beryl Benacerraf observed

presence of thick nuchal fold in
utero during second trimester
Ultrasound

• Absence of nasal bone was

observed in trisomy fetuses in utero
 MATERNAL AGE
The risk for trisomy 21
 Increases with maternal age
 Back ground ( apriori risk )
 Decreases with gestational age because
about 30% of affected fetuses die between
the 12th and 40th week of pregnancy

• The risk for trisomy 21 increases with

maternal age with 30% risk of DS only the
vast number is at age < 35 yrs so 70%
chances
• UNIVERSAL SCREENING TO BE
NUCHAL TRANSLUCENCY SCREENING
 Description- Echo free fluid filled area seen between soft
issue and skin at the back of the neck by ultrasound .
Does not matter if septated or not
 Indication – should be offered to all pregnant women
 Interpretation- ONLY SIZE MATTERS NOT LOOK
- A NT >3 mm is abnormal (~1.8-2 MoM)
-Larger the NT higher the aneuploidy risk
-Can be associated with CHD , skeletal dyplasia,
abdominal wall defect etc
- Can be associated with genetic syndrome like Noonan’s
- Best method available for twins
 Aneuploidy detect rate – 65-70% with absence of nasal
bone a strong pointer
 Limitations- Operator dependent and needs strict
protocol & not all women visit for antenatal care so
early.
-
 IMAGE SPECIFICATIONS
• TIMING MATTER ?
Best Timing – B/w 11- 13wks+6d
• SIZE MATTERS ?
CRL b/w 45-84mm
• MAGNIFICATION MATTERS ?
2/3rd magnification , 1/3rd chest seen
• POSITION MATTERS ?
Mid sagittal & neutral position
• CALIPER PLACEMENT MATTERS ?
Gain down , widest part and in to in
• RULE OUT AMNION AND CORD
• AVERAGE OF 3 MEASUREMENTS
NUCHAL TRANSLUCENCY
Nuchal thickness increases with CRL in euploid
The median NT for euploid =2.0 mm
For trisomy 21 =3.4 mm
For trisomy 18= 5.5 mm
For trisomy 13 =4.0 mm
For turners Syn = 9.2 mm resp.
In 75-80% of trisomy 21 fetuses the NT thickness is
above the 95th centile of the normal range (3-3.4mm).
The 99th centile is about 3.5 mm and
does not change with CRL
IF RAISED NT BUT NORMAL
CHROMOSOMES ON DIAGNOSTIC TEST
• More than 50 fetal defects ( CHD , skeletal dysplasias , GI defects )and genetic
syndromes.( Noonans syndrome , Non immune hydrops spectrum etc)
• 20-30% have adverse pregnancy outcome eg IUFD, PRETERM , LBW
• Fetal death.
• However, in the majority of cases the NT resolves and the babies are born healthy.
ALL TESTS NORMAL BUT NUCHAL EDEMA
PERSISTS
• Increase chances of perinatal death
 NASAL BONE
 Done at the same plane as of CRL and NT

• At 11-13 weeks the nasal bone is considered to be absent in about:

Euploid fetuses 1-3%
Fetuses with trisomy 21 60%
Fetuses with trisomy 18 50%
Fetuses with trisomy 13 40%
Baby of Black woman might have small or absent nasal bone

• Assessment of the nasal bone improves the performance of combined screening

increasing the detection rate from 90% to 94% and decreasing the false positive
rate from 3% to 2.5%
NEEDS EXPERTISE AND SPECIAL TRAINING TO MASTER IT
DUCTUS VENOSUS
 A small vessel connecting
umbilical vein to the IVC
 Represents the hemodynamic
status of a normal and abnormal
heart .
 Aneuploidy fetuses shows
abnormal ductus venosus flow
which is represented as reversed
‘a’ waveform on dopplers
 Strict specifications needed in its
evaluation
 DUCTUS VENOSUS REVERSED A-WAVE FORM
Absent
Reversed ora-wave
reversed a-wave and High PI
increase risk of :
At 11-13 weeks reversed a-wave is found in about:
• Chromosomal abnormalities
 Euploid fetuses 3%
• Сardiac defects
 Fetuses with trisomy 21 ~ 65%
• IUGR
• Fetuses with trisomy
Fetal death- Assess18 ~PAPP-A
55% value-
 Fetuses
If low with trisomy 13 ~55%
-Monitor
Reversed fetal
a-wavegrowth
is more
(scan
common
at 20, 28
if: & 34
wks)
 The uterine
gestationA
is PI & fetal
11 than Dopplers
13 weeks Assessment of DV a-wave improves
However, in about
 The fetal nuchal 80% of iscases
translucency high with the performance of first-trimester
combined screening:
reversed a-wave
 The maternal serum thePAPP-A
pregnancy
is low outcome is Detection rate 95%
normal False positive rate 2.5%
 TRICUSPID FLOW

• Represents the status of right heart and

flow across it. The flow gets affected in
aneuploidies and various cardiac
conditions.
• Different flow from pathological

At 11-13 weeks tricuspid regurgitation is

found in about:
Euploid fetuses 1%
Fetuses with trisomy 21 55% Assessment of the tricuspid flow improves the
performance of combined screening increasing
Fetuses with trisomy 18 30% the detection rate from 90% to 95% and
decreasing the false positive rate from 3% to
Fetuses with trisomy 13 30% 2.5%
 SERUM MARKERS
WHERE DO THEY COME FROM ?

FIRST TRIMESTER SECOND

(11-13wks +6D) TRIMESTER
Indication- Should be offered (15wks- 20 wks+6d)
to all pregnant women Indication- Only when 1st
DUAL TEST trimester screening missed or
• Free β HcG competent sonologist NA
• PAPP-A QUADRUPLE TEST
others • Free β HcG
• AFP , PLGF • AFP
• INHIBIN –A • uE3
Detection rate- 60-65% • Inhibin –A

DETECTION RATE- 75-

1ST TRIMESTER Marker values IN T21,T18, T13
Considering for Euploid fetus the
value of Free ββHcG is 1MoM &
PAPP-A is 1 MoM
SECOND TRIMESTER SERUM SCREENING
 INDIVIDUAL INTERPRETATION OF SERUM MARKERS
PAPP-A –
<0.45 MoM (5th percentile)
- 1 to 4% risk of pregnancy loss before 20 weeks
- increased risk pathological
*ALSO, of intrauterine
lowgrowth
level ofrestriction,
PAPP-A ifpositive predictive
<0.5 MOM (normalvalue 14% has
= 1MOM)
- increased
beenrisk of preterm
associated withdelivery before fetal
other adverse 34 weeks
outcomes and thrombophilia and
<0.29 MoM (1stcan
patients percentile)
be empirically started on LDA & LMW Heparin.
- significantly increased risk of intrauterine growth restriction, with positive predictive
values of 24%
-
MATERNAL SERUM SCREENING

PROS CONS LIMITATIONS

• Noninvasive • Increases anxiety • Only 60-65%
• Easily available • False reassurance detection rate with
• Less operator 5% FPR in 1st
dependent trimester
• Does identify fetus at • Quad test- 80%
risk • Lab matters
• Serum markers can
be used in
individually
WHAT & WHY IT IS IMPORTANT ??
 EARLY DIAGNOSIS OF MAJOR DEFECTS AT 11-14wks

Some of these abnormalities are associated with

increased NT:
• Major cardiac defects
• Diaphragmatic hernia
• Exomphalos
• Megacystis
• Body stalk anomaly
• Skeletal abnormalities
In other abnormalities fetal NT is usually normal:
• Acrania / anencephaly
• Ventriculomegaly
• Holoprosencephaly
• Spina bifida
• Gastroschisis
 DIFFERENCES BETWEEN ALL TRISOMIES

 There are differences between the three

trisomies:
 Fetal NT is higher in trisomies 18 and
13 than in trisomy 21
 Serum PAPP-A is lower in trisomies 18
and 13 than in trisomy 21
 Serum free ß-hCG in trisomy 21 is high
whereas in trisomies 18 and 13 this is
low
 Fetal heart rate in trisomy 13, unlike
trisomies 21 and 18, is high
STEPWISE FT TRISOMY 21 SCREENING (OPTIMAL TIME)
Maternal age -30%DR
H/O downs baby If NT appears increased Look for other USG features –
add NB, TR,DV ,aberrant megacystis,CHD,Echogenic
Gestational age RSA,FHR bowel, Pelviectasis
Smoker,obese,ART

11- 14wks (12-13wks Measurement

DUAL TEST –βHcG+ PAPP-A
Best time ) -correlated with GA
IN T21- 2xβHcG &1/2 PAPP-
45-84 MM CRL ->3.5mm is above 99th centile A
CRL QUALITY
60-70%DR WITH 5%FPR
-Magnification COMBINED TEST
Nuchal Translucency SCREENING -85-95 %DR
-Sagittal section & WITH 5%FPR
measurement from a
certified operator -Neutral position Adding additional
Caliper placement USGmarkers-94-96% AT
2.5%FPR

75-80 % DR WITH 5%FPR UNCOMPROMISABLE

 RISK STRATIFICATION

Every woman has a risk that her fetus/baby has a chromosomal defect .

The background or A PRIORI RISK depends on maternal age and gestation

The LIKELIHOOD RATIO for a given sonographic or biochemical measurement is

calculated by dividing the percentage of chromosomally abnormal fetuses by the
SOFTWARE
percentage of normalIS REQUIRED
fetuses FOR RISK
with that measurement.
CALCULATION
Every time a test is carried out the a priori risk is multiplied by the likelihood ratio
of the test to calculate a new risk, which then becomes the a priori risk for the next
test.

The INDIVIDUAL PATIENT-SPECIFIC RISK is calculated by multiplying the a

priori risk with a series of likelihood ratios, which depend on the results of a series
of ultrasound and serum markers used as screening tests in first trimester.
FETAL FRACTION SHOULD BE
>10-15%
Not applicable for-
• H/o recurrent miscarriages
• Family h/o genetic disease
• Ultrasound showing malformation
• Increased NT or nuchal fold thickness
RISK STRATIFICATION USING COMBINED SCREENING + NIPS
 SECOND TRIMESTER GENETIC SCREENING
CONSTITUTE MAJOR SOFT MARKERS
S: MARKERS
 These are less-defined USG features that If increase NFT ,
When isolated small NB ,
have been given less significance as marker found –
“possible markers” of aneuploidy, prenasal edema
further Mgt LR high(>10)
 Although not pathologic ( structurally or depends on the then NIPS/
functionally ) themselves, these markers type and its LR invasive testing
have been used to screen for, or adjust
the risk for, Down syndrome and other If EIF, short long
aneuploidies. bone , mild If > 1soft
 Soft markers may be seen in the normal pyelectasis marker present
fetus but have an increased incidence in present , there is advice invasive
infants with chromosomal abnormalities. no increase or testing
decrease in risk
MAJOR AND SOFT MARKERS IN GENETIC SCAN

Absent ot Hypoplastic nasal

bone & prenasal edema
( >5mm) (<4.5mm)
SOFT MARKERS
SOFT MARKERS
SPECIAL SITUATION – TWIN PREGNANCY
 TAKE HOME MESSAGE(MULTIPLE PREGNANCY)
 The maternal age for intensive screening in twins is decreased to 3 years that is
32 yrs and for triplets it is 29 yrs and so on.
 In twins combined screening For DCDA its fetal risk and for MCDA it is
pregnancy risk ) but not applicable for triplets or more where MA + NT IS
APPLICABLE .
 In DC twins the normal twin masks the detection rate of affected twin
, so DR is 84% in MC , 70% in DC and 72% overall with 5% FPR
 In case of vanishing twin biochemistry only if fetal pole not visible (>8wks of
fetal demise) else only NT evaluation
 Role of QUAD TEST AND NIPT needs validation
 Invasive testing is preferred if high risk assessed
SPECIAL CONDITION- IVF PREGNANCIES
 TAKE HOME MESSAGE
All pregnant women to be offered aneuploidy screening with pretest counseling

First trimester maternal age + NT + serum screening – BEST RESULTS

Triple marker out , QUAD or Integrated screening only if NT not done /late ANC

NT + USG markers assessment to be done as per FMF guidelines

Serum markers to be read in combo as well individually FOR fetal risk assessment

Contingent screening is the best method for fetal risk evaluation and counselling

Timing , sampling & accredited LAB with good software decrease FP & anxiety

Chorionicity to be determined in first trimester & NT + Dual test best method

 TAKE HOME MESSAGE
Any soft marker presence is not an indication for termination but further testing

NIPS can be offered to highrisk /low risk women with pre& post test counseling

NIPS only detect 5 common ch disorder ( T21,T18,T13 , X &Y) no other

NIPS also being used of Rh typing and sex determination for genetic dis.

.All screen positive results must be confirmed by invasive testing

Termination of pregnancy not on +ve screening test report how high it may be

TRY TO FINISH ALL TESTS BEFORE 20 WKS OF GESTATION

INTERPRETATION OF MOM VALUES & RISK OF
ANEUPLOIDY
MoM (multiple of median) - result reported strictly as multiple of median
MoM’s vary with gestational age ,with assay method , with population tested
May need adjustment for:
– weight – ethnic group – other conditions e.g. diabetes – twin pregnancies - ART

- In screening using maternal serum biochemical markers, the measured concentration of the markers is
converted into a multiple of the median (MOM) of unaffected pregnancies at the same gestation.
- The Gaussian distributions of log10 (MoM) in trisomy 21 and unaffected pregnancies are then derived,
and the ratio of the heights of the distributions at a particular MoM, which is the likelihood ratio for
trisomy 21.

-It is used to modify the a priori maternal age-related risk to derive the patient-specific risk.
 General principles
 Every woman has a risk that her fetus/baby has a chromosomal defect.
 The a priori risk depends on maternal age and gestation.
 The patient-specific risk is calculated by multiplying the a priori risk with a series of likelihood
ratios, which depend on the results of a series of screening tests.
 The likelihood ratio for a given sonographic or biochemical measurement is calculated by dividing
the percentage of chromosomally abnormal fetuses by the percentage of normal fetuses with that
measurement.
 Every time a test is carried out the a priori risk is multiplied by the likelihood ratio of the test to
calculate a new risk, which then becomes the a priori risk for the next test.
 If the tests are not independent of each other then more sophisticated techniques, involving
multivariate statistics, can be used to calculate the combined likelihood ratio.
If the translocation is de novo
and neither parent has a balanced translocation, then there is
no increased risk of recurrence. If the mother carries a balanced
translocation, then the risk for future pregnancies is about 10%
to 15%, whereas if the father carries the balanced translocation,
the risk is about 3% to 5%.4 Rarely, the translocation involves
both of the chromosomes 21. In this circumstance, the carrier parent of the 21/21
translocation would have a 100% risk
of recurrence. There is not an increased rate of trisomy 21 in
second-degree relatives.24
COMMON FEATURES OF MAJOR TRISOMIES
Recommendations
1. EICF should be evaluated as
part of the 4-chamber cardiac
review during the 16- to 20- week
ultrasound (III-B).
2. 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).
3. 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 (II-2 B).
4. Women with right-sided,
biventricular, multiple,
particularly conspicuous, or
nonisolated EICF should be
Recommendations
Recommendations 1. Assessment of cord vessels
1. Evaluation of fetal kidneys is a part is considered a part of the
of the screening ultrasound at 16 to routine obstetric ultrasound at
20 weeks,’ and if pyelectasis is 16 to 20 weeks (III-A).
visualized, the 2. The finding of a single
renal pelvis should be measured in umbilical artery requires a
the anterior/posterior more
diameter (III-B). detailed review of fetal
2. All fetuses with renal pelvic anatomy, including kidneys
measurements 5 mm and
should have a neonatal ultrasound, heart (fetal echo) (II-2 B).
and those having measurements > 10 3. An isolated single umbilical
mm should be considered for a third artery does not warrant
trimester scan (II-2 A). invasive testing for fetal
3. Isolated mild pyelectasis does not aneuploidy (II-2 A).
require fetal
karyotyping (II-2 E).
4. Referral for pyelectasis should be
considered with additional ultrasound
findings and (or) in women at
increased
 Recommendations
mmendations Recommendations
1. Fetal cerebral ventricles should be
aluation of the fetal bowel should be done routinely 1. Nuchal fold
measured if they subjectively appear large
g the 16- to 20-week obstetric ultrasound (III-B). measurement should be a
than the choroid plexus (III-B).
hogenic bowel should be identified by comparison part of the screening
2. Cerebral ventricles greater than or equa
the echogenicity of surrounding bone using an appropriate obstetric ultrasound at 16
to 10 mm are
ducer and gain setting. Bowel echogenicity equal to 20 weeks (III-B).
associated with chromosomal and central
greater than bone is significant (grade 2 or 3) (II-2 A). 2. A thickened nuchal fold
nervous system
o further investigations are required for grade 1 significantly increases the
pathology. Expert review should be
genic bowel (II-2 D). risk of
initiated to obtain the
ade 2 and 3 echogenic bowel is associated with both fetal aneuploidy. Expert
following: a. a detailed anatomic
mosomal and nonchromosomal abnormalities. Expert review is recommended,
evaluation looking for
w is recommended to initiate the following: a. detailed and
additional malformations or soft markers
sound evaluation looking for additional structural karyotyping should be
(III-B); b. laboratory investigation for the
malies or other soft markers of aneuploidy (II-2 A); b. offered (II-1 A).
presence of congenital infectionor fetal
led evaluation of the fetal abdomen looking for signs 3. A thickened nuchal fold
aneuploidy (III-B); and c. MRI as a
wel obstruction or perforation (II-2 B); and c. detailed is associated with
potential additional imaging technique (II-
uation of placental characteristics (echogenicity, thickness, congenital
2 C).
ion, and placental cord insertion site) (II-2 B); d. heart disease and rarely
3. Neonatal assessment and follow-up are
tic counselling (II-2 A); e. laboratory investigations that with other genetic
important to rule out associated
d be offered, including fetal karyotype, maternal syndromes.
abnormalities and are important because o
m screening, DNA testing for cystic fibrosis (if appropriate), Expert review is
the potential for subsequent abnormal
esting for congenital infection (II-2 A). recommended (II-2 B).
neurodevelopment
 Recommendations Recommendations
1. Review of the fetal cerebellum 1. Although femur length is standard
and cisterna magna is a week ultrasound, the assessment for
Recommendations
routine part of the screening part of the screening evaluation (III-
1. Choroid plexus should be evaluated for the
ultrasound at 16 to 20 weeks. 2. Relative femur shortening is an u
presence of
Enlarged cisterna magnaIf the trisomy 21 and should be considered
discrete cysts during the 16- to 20-week ultrasound
cisterna magna is subjectively evaluation (II-1 A).
(III-B).
increased, a measurement should be3. If a femur appears abnormal or m
2. Isolated CPCs require no further investigation
taken (III-B). screening ultrasound, other long bon
when maternal age or the serum screen equivalent is
2. An isolated enlarged cisterna referral with follow-up ultrasound c
less than therisk of a 35-year-old (II-2 E).
magna is not an indication
3. Fetal karyotyping should only be offered if isolated
for fetal karyotyping (III-D). Recommendations
CPCs
3. With an enlarged cisterna magna, 1. Humeral length is not part of th
are found in women 35 years or older or if the
expert review is recommended for at 16 to 20 weeks but should be co
maternal serum screen is positive for either trisomy
follow-up ultrasounds and possible (III-B).
18 or 21 (II-2 A).
other imaging modalities (for 2. Relative humeral shortening is a
4. All women with fetal CPCs and additional
example, MRI) and investigations trisomy 21 and should be consider
malformation should be offered referral and
(III-B). evaluation (II-1 A).
karyotyping (II-2 A).
4. If the enlarged cisterna magna is 3. If the humerus is evaluated and
5. All women with CPCs and additional soft markers
seen in association with short, other long bones should be a
shouldbe offered additional counselling and further
other abnormal findings, fetal follow-up ultrasound considered (I
ultrasound
karyotyping should be
review (III-B).
offered (III-B).
 For isolated abnormalities the likelihood ratio for trisomy 21 is:

Recommendations About 1 (therefore the a priori risk is not increased) in the case
1. Assessment of the fetal nasal of choroid plexus cysts, echogenic endocardiac focii, mild
bone is not considered a hydronephrosis and short femur.
part of the screening ultrasound at About 10 (therefore there is a 10-fold increase in the a priori
16 to 20 weeks (III-B). risk) for nuchal or prenasal edema and hypoplastic nasal bone.
2. Hypoplastic or absence nasal
bone is an ultrasound
marker for fetal Down syndrome,
and if suspected, expert
review is recommended (II-2 B)
ARSA
Figure 2 Normal meiosis (left) and nondisjunction (right). Only one of the 23 chromosome pairs is demonstrated;
assume all other chromosome pairs
undergo normal meiosis. Numbers reflect the total number of chromosomes in the gamete at that stage in meiosis.
 • Dimeric glycoprotein hormone (α & ß subunits) secreted by the
fertilised ovum and later by placental tissue.
• Maternal serum hCG maximal during first trimester, then
Free declines during second trimester
• Overall, in Trisomy 21 ßhCG values are higher, those higher than
βHcG 2.5 MoM indicating a possible pathology. In Trisomies 13 and 18,
these values are generally low, with suspicious values being those
below 0.4 MoM.

• It is a glycoprotein synthesized in chorionic villi of the placenta.

This protein is a key regulator of IGF bio-availability essential
for normal fetal development.
PAPP-A • It continues to increase during the pregnancy period and
declines after delivery.
• When PAPP-A is low ( < 0.4 MoM )the risk for Down syndrome is
increased and when it is elevated, the risk is reduced.
LEFTTOPICS

 Cell free DNA

 ARSA
 TRANSLOCATION
 MEIOSIS
 READFROM PALADINI