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The Fetal Medicine Foundation

The First Trimester Screening module UPDATE 2008 to 2009 algorithm

This guide has been written to highlight the new features of this latest version of the module and to
make sure that the clinicians understand the basis of the risks they are providing.
It is not intended to teach you all there is to know about First Trimester Screening – it is essential that
all those using the module attend the 11-13 weeks FMF internet course
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/) and obtain the
Certificate of Competence in the 11 – 13 weeks scan (http://www.fetalmedicine.com/fmf/training-
certification/certificates-of-competence/the-11-136-week-scan/). Neither is it designed to tell you
how the program works – astraia has done this in the user guide, setting out the program functions,
screen by screen (see Help pages).

The Fetal Medicine Foundation has released an improved 1st Trimester algorithm (FMF 2009).
There are no changes to risk calculation by nuchal translucency and other ultrasound markers.

The new software has incorporated the latest research publications to allow calculation of risks for
preeclampsia and gestational hypertension based on first trimester assessment. The previous version
included risk calculation by maternal history. PAPP-A and uterine artery mean PI only. This has been
extended to include all combinations of maternal history, uterine artery Doppler (lowest PI), mean
arterial pressure (MAP), PAPP-A and PlGF (placental growth factor). Risks are calculated for early
preeclampsia, early + late preeclampsia and all hypertensive orders (preeclampsia and gestational
hypertension). The detection rates and false positive rates for each combination are available in the
program help pages.

There has also been an improvement in the algorithm for the calculation of risks for chromosomal
abnormalities. In the previous version the biochemical parameters for pregnancies before 11 weeks
were derived from the extrapolation of available data from 11-13 weeks. Data comprising tens of
thousands of patients examined before 11 weeks have now been made available to the FMF and on
the basis of such data it was possible to now produce new algorithms that describe well the distribution
of measurements from 8 to 14 weeks.

Another important function of the new software is the ability of individual centres to monitor their
median values of free beta hCG and PAPP-A and adjust the values themselves. An adjustment of
between 0.85 to 1.15 on individual MoMs can be made; this can be calculated from the past year's
data, provided at least 1000 cases have been analysed in the last six months.

A new FMF license format has been created, which will be common to all software manufacturers.
Licenses will be user- rather than centre-based, allowing users to add their personal license to all
installations where they work. To make life easier, this license can be directly downloaded from the
FMF web site into the program. Users without internet access at the program site can download the
license file from the website and import it as a file.

Individual risks (ultrasound-only and biochemistry-only) have been dropped because they sometimes
lead to confusion, and because the FMF software description does not specify how they should be
calculated.

The calculation of gestational age from CRL has been modified to agree with the UK National
Screening Program guidelines (this is very small change, resulting in at most one day difference in
gestational age).

More languages have been added and existing translations have been improved.

The default risk cut-off for trisomy 21 is now 1 in 100 (or 1 in 150 at term), as recommended by the
FMF and the UK National Screening Program guidelines. Existing users are recommended to change

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their setting to reflect this, as otherwise an increased false-positive rate will result.

The export file (used when submitting data for audit, and for analysis of screening data) has been
extended to include values and MoMs for uterine artery Doppler, mean arterial pressure and PlGF, and
biochemistry adjustment factors used in MoM calculations.

1. DEMOGRAPHIC DETAILS

Ethnicity - Ethnic group

The prevalence of absent fetal nasal bone varies with the ethnic origin of the mother. In addition,
maternal ethnic group has a major influence on maternal serum biochemistry. Therefore, it is important
to accurately record the ethnic group of the mother. The lists in the risk calculation are fixed, to ensure
that the risks are adjusted appropriately and the mother should be categorised using the following:

• White (European, Middle Eastern, North African, Hispanic)
• Black (African, Caribbean, African American)
• East Asian (Chinese, Japanese, Korean)
• South Asian (Indian, Pakistani, Bangladeshi)
• Mixed (White-Black, White-East Asian, White-South Asian, Black-East Asian, Black-South
Asian, East Asian-South Asian)

IMPORTANT: If any other category is added, the nasal bone, ductus venosus and serum biochemistry
will not be taken into account for the risk calculation.

References:
Spencer K, Heath V, El-Sheikhah A, Ong CYT, Nicolaides KH. Ethnicity and the need for correction of
biochemical and ultrasound markers of chromosomal anomalies in the first trimester: a study of
oriental, asian and afro-caribbean populations. Prenat Diagn 2005;25:365-369.

Kagan KO, Wright D, Spencer K, Molina FS, Nicolaides KH. First-trimester screening for trisomy 21 by
free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A: impact of
maternal and pregnancy characteristics. Ultrasound Obstet Gynecol. 2008;31:493-502.

Kagan KO, Cicero S, Staboulidou I, Wright D, Nicolaides KH. Fetal nasal bone in screening for
trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol.
2009;33:259-64

Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for
trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol.
2009 May;33(5):512-7.

Assisted conception

Maternal age and pregnancy dating are often issues complicating risk calculation in IVF pregnancies.
Dating in IVF pregnancies is simple as the exact gestational age should be known and there is never
an indication to date / redate by CRL. The most accurate way to date an IVF pregnancy is to create an
EDD using the date of embryo transfer minus 14 days plus 280 days. The software will now do this
automatically if date of embryo transfer is entered.

With regard to maternal age, it is important to know whether the cycle used the mother’s own eggs, or

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those of a donor and whether the eggs were frozen and, if so, for how long. The program will now allow
you enter the correct DOB for the mother, as well as the donor’s DOB if you indicate that donor eggs
have been used. The risk calculation will then use the donor’s age to generate the a priori risk. If the
exact donor DOB is not known, the software will generate a risk based on the donor's age and assume
that she is midway between birthdays. Similarly, the program will correctly adjust the a priori risk if the
eggs have been frozen. There is no longer a need to adjust the mother’s DOB manually to take into
account these two factors.

Note:

In previous versions of the software biochemical MoMs were affected by IVF pregnancy. A new field -
Ovulation induction, has been added as this is the factor affecting both MoMs and risk for
preeclampsia, irrespective of the method of conception.

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2. FIRST TRIMESTER SCAN

Fetal heart rate

Fetuses with trisomy 21 (T21) have a slight increase in heart rate. However, fetuses with trisomy 13
(T13) have a significantly increased heart rate (75% of fetuses with T13 have a FHR > 175 bpm) and
the fetal heart rate improves detection of T13. A fetus noted to have a high heart rate should be
examined carefully for markers of chromosomal abnormality.

Reference:

Kagan KO, Wright D, Valencia C, Maiz N, Nicolaides KH. Screening for trisomies 21, 18 and 13 by
maternal age, fetal nuchal translucency, fetal heart rate, free beta-hCG and pregnancy-associated
plasma protein-A. Hum Reprod 2008;23:1968-75.

Crown-rump-length

The First Trimester scan can only be performed when the crown-rump length (CRL) is between 45.0
and 84.0mm. It is very important that the CRL is measured accurately. The algorithm for the
calculation of risk using NT includes the CRL measurement and even a small difference in the
measurement can have a significant affect on the risk. For example, in a 40 year old woman at 12
weeks with an NT of 2.0mm, if the CRL is measured as 50mm, the risk is 1 in 50, but if the CRL is
70mm, the risk becomes 1 in 287.

The CRL should be measured with the fetus in a neutral position:

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Nuchal translucency

When using the FMF risk calculation software, it is essential that the FMF guidelines for the
measurement of NT are followed correctly. An individual will only be given a license to use the risk
calculation software if they hold the FMF certificate of competence in the 11 – 13 weeks scan.

The most important change to the program has been the introduction of the mixture model of NT
distributions: The distribution of NT with CRL in both normal and trisomic fetuses follows two distinct
patterns:
• In 95% of T21, 70% of T18, 85% of T13 and 5% of chromosomally normal fetuses the fetal NT
is high and independent of CRL.
• In 95% of the chromosomally normal group, 5% of T21, 30% of T18 and 15% of T13 there is an
identical pattern in NT which increases with CRL.

Fetuses with an increased NT but normal karyotype have a higher incidence of adverse outcome
compared with fetuses with a NT measurement within the normal range. Abnormalities include major
cardiac defects, musculo-skeletal abnormities, fetal infection and rare genetic syndromes, as well as an
increase risk of fetal death. Therefore a detailed anomaly scan, including thorough cardiac evaluation,
is recommended for all fetuses with an NT > 95th centile. However, if the karyotype is normal, the
increased NT has resolved by 20 weeks and no structural defects are seen, the prognosis is very good
and the long term prognosis is similar to that of fetuses with normal NT.

For the latest information, please see on the Fetal Medicine Foundation website
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

References:
Wright D, Kagan KO, Molina FS, Gazzoni A, Nicolaides KH. A mixture model of nuchal translucency
thickness in screening for chromosomal defects. Ultrasound Obstet Gynecol. 2008;31:376-83.

Souka AP, Von Kaisenberg CS, Hyett JA, Sonek JD, Nicolaides KH. Increased nuchal translucency
with normal karyotype. Am J Obstet Gynecol. 2005;192:1005-21.

Nuchal cord

A nuchal cord is present in about 5% of pregnancies. The cord has often moved if the patient is
scanned later and it does not obviously cause the poor fetal outcome associated with cord accidents.
However, it may make the NT difficult to interpret: in this situation the NT must be measured above and
below the cord and the average is used in the risk calculation. The new software will make this

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calculation of the mean for you as long as the NT max and NT min are correctly entered when
prompted.

Nasal bone

At 11 – 13 weeks the nasal bone (NB) is not visible by ultrasound in about 60% of fetuses with T21,
50% with T18 , 40% with T13 and in about 2% of chromosomally normal fetuses. Therefore, the
presence of the fetal nasal bone will reduce the risk for T21. The prevalence of absent NB varies with
maternal ethnic origin, so it is important to correctly attribute maternal ethnic group. The software will
not use the fetal nasal bone in the risk calculation if the ethnic group is not entered using the grouping
provided.

It is essential that the FMF guidelines for the measurement of nasal bone are followed correctly and the
findings on NB will only be taken into account in the risk assessment if you hold the FMF certificate of
competence in NB have the NB included in your license.

For the latest information, please see on the Fetal Medicine Foundation website
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

References:

Cicero S, Avgidou K, Rembouskos G, Kagan K, Nicolaides KH. Nasal bone in first-trimester screening
for trisomy 21. Am J Obstet Gynecol 2006;195:109-14

Kagan KO, Cicero S, Staboulidou I, Wright D, Nicolaides KH. Fetal nasal bone in screening for
trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol
2009;33:259 -64

Tricuspid regurgitation

Tricuspid regurgitation (TR) is observed in about 55% of fetuses with T21, 30% of fetuses with T18 and
T13 and in 1% of chromosomally normal fetuses.

It is essential that the FMF guidelines for assessment of TR are followed correctly. The presence or
absence of TR will only be taken into account in the risk assessment if you hold the FMF certificate of
competence in TR assessment and have the TR included in your license.

TR is associated with cardiac defects and therefore when TR is noted at the 11 – 13 weeks scan, it is
important to carry out a good fetal cardiac examination at 20 – 23 weeks.

For the latest information, please see on the Fetal Medicine Foundation website
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

Reference:

Kagan KO, Valencia C, Livanos P, Wright D, Nicolaides KH. Tricuspid regurgitation in screening for
trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation. Ultrasound Obstet
Gynecol 2009;33:18-22

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Ductus venosus

Blood flow in the ductus venosus (DV) has a characteristic waveform with high velocity during
ventricular systole (S-wave) and diastole (a-wave). At 11 – 13 weeks reversed a-wave in the DV is
observed in about 3% of chromosomally normal fetuses, 65% of fetuses with T21, 55% of fetuses with
trisomy 18 and 55% of fetuses with trisomy 13.

It is essential that the FMF guidelines for the assessment of the DV are followed correctly and the DV
assessment will only be taken into account in the risk assessment if you hold the FMF certificate of
competence in DV assessment and have the DV included in your license. Furthermore the ethnic group
needs to be filled out.

Reversed a-wave in the DV is associated with cardiac defects and therefore when this pattern is noted
at the 11 – 13 weeks scan, it is important to carry out a good fetal cardiac examination at 20 – 23
weeks.

For the latest information, please see on the Fetal Medicine Foundation website
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

References:

Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for
trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation. Ultrasound Obstet Gynecol.
2009;33:512-7.

Maiz N, Plasencia W, Dagklis T, Faros E, Nicolaides K. Ductus venosus Doppler in fetuses with cardiac
defects and increased nuchal translucency thickness. Ultrasound Obstet Gynecol 2008;31:256-60

Fronto-maxillary-facial angle

In fetuses with T21 the flat profile is caused in part by a small maxilla, set back from the other facial
bones. This causes an increase in the fronto-maxillary facial angle – the angle is above the 95th centile
of the normal range in about 50% of fetuses with T21.

It is essential that the FMF guidelines for the measurement of FMF angle are followed correctly (see
appendix 5) and the FMF angle measurement will only be taken into account in the risk assessment if
you hold the FMF certificate of competence in FMF angle measurement and have the FMF angle
included in your license.

Only the T21 risk is affected by the FMF angle, whereas the risks for T13 and T18, in addition to the
T21 risk, are affected by NB, TR and DV.

For the latest information, please see on the Fetal Medicine Foundation website
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

References:

Borenstein M, Persico N, Kagan KO, Gazzoni A, Nicolaides KH. Frontomaxillary facial angle in
screening for trisomy 21 at 11 + 0 to 13 + 6 weeks. Ultrasound Obstet Gynecol 2008;32:5-11

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Major markers

Certain major defects have a very strong association with chromosomal abnormalities and therefore the
risk for the typical chromosomal abnormality is fixed irrespective the other ultrasound or biochemical
findings.

The major markers include:
• Holoprosencephaly
• Diaphragmatic hernia
• Atrioventricular septal defect
• Exomphalos
• Megacystis

They can be considered in isolation, but the finding of one marker should prompt a very thorough
examination of the fetus looking for other markers. The risks are as follows:

Major marker Fixed risk
T21 T18 T13
Holoprosencephaly - - 1 in 2
Diaphragmatic hernia - 1 in 4 -
AVSD 1 in 2 - -
Exomphalos - 1 in 4 1 in 10
Megacystis - 1 in 10 1 in 10
Exomphalos and megacystis - 1 in 3 1 in 3
Holoprosencephaly and exomphalos / megacystis - - 1 in 2
Diaphragmatic hernia and exomphalos / megacystis - 1 in 2 -

If other ultrasound or biochemical markers are abnormal and the calculated risk is higher than the fixed
risk, then the calculated risk will be applied.

Exomphalos
A finding of exomphalos increases the risk of trisomy 18 to 1 in 4 and the risk of trisomy 13 to 1 in 10,
regardless of the other ultrasound and biochemical findings.

An exomphalos is seen in 1 in 1000 pregnancies between 11 – 13 weeks. 60% of these will have a
chromosomal abnormality, most commonly T18. However care must be taken not to mistake a
physiological exomphalos for a pathological one and when the CRL is less than 55mm and an
exomphalos containing only bowel is recorded, the following warning message will be displayed:
“Please rescan in one week to confirm because in the majority of cases the exomphalos may resolve.
The finding of exomphalos today will not change the risk”. This message does not appear and the risk
will be recalculated if it is documented that the exomphalos contains liver.

Megacystis
The fetal bladder can be visualised in 80% of fetuses at 11 weeks and in all cases by 12 weeks. At this
gestation the fetal bladder length is usually less than 7mm. The bladder length is 7mm or more in 1 in
1500 pregnancies. In 20% of cases where the bladder length is between 7 and 15mm, there is T13/18,
but 90% of those with a normal karyotype resolve spontaneously with good fetal outcome. Conversely
those with a bladder length of more than 15mm have only a 10% risk of T13/18, but most go on to
develop a progressive obstructive uropathy.

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Diaphragmatic hernia
Increased NT thickness is present in about 40% of fetuses with diaphragmatic hernia, including more
than 80% of those that result in neonatal death due to pulmonary hypoplasia and in about 20% of the
survivors. This suggests that the fetuses with diaphragmatic hernia and increased NT have
intrathoracic herniation of the abdominal viscera in the first trimester and prolonged compression of the
lungs causes pulmonary hypoplasia.

Minor markers

Minor markers are fetal anomalies of no pathological significance in themselves but are found more
commonly in chromosomally abnormal than normal fetuses. They are traditionally considered as
second-trimester markers but they can now be seen in the first trimester.

The minor markers considered significant include:
• Choroid plexus cyst (>1.5mm)
• Echogenic intracardiac focus
• hyperechogenic bowel
• hydronephrosis (antero-posterior diameter >1.5mm)

The finding of one or more of these markers should prompt a very thorough scan of the rest of the
fetus, looking for other markers of chromosomal abnormality. The absence of each marker is
reassuring and therefore acts to counterbalance any possible increased risk that the presence of the
one marker may have suggested. Therefore it is essential that none of these should be considered in
isolation, but as a group and the risk will only be adjusted if this is done. Conversely if no soft markers
are found, the risk can be reduced.

Soft markers are only included in the risk calculation for T21 and not for T13/18, although it should be
noted that CPCs have a stronger association with T18 rather than T21 and therefore the finding of
CPCs should prompt a thorough examination to exclude any other markers of T18.

References:

Dagklis T, Plasencia W, Maiz N, Duarte L, Nicolaides KH. Choroid plexus cyst, intracardiac echogenic
focus, hyperechogenic bowel and hydronephrosis in screening for trisomy 21 at 11 + 0 to 13 + 6 weeks.
Ultrasound Obstet Gynecol 2008;31:132-5.

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3. MATERNAL SERUM BIOCHEMISTRY

MoM (multiple of the median)

Biochemical MoMs are calculated using the gestational age derived from CRL, regardless of the
clinical decision about how to date the pregnancy.

Important: MoMs will only be calculated if all of the below data set is entered

* Sample taken
* Gestational age
* Maternal weight (in kg)
* Ethnic group
* Smoking (yes / no)
* IVF (yes / no)
* Parity (nulliparous / parous)
* Number of fetuses (automatically recorded)
* Equipment (Brahms Kryptor or Delfia Xpress)
* Chorionicity in the case of twins

Biochemistry MoMs
The measured concentration of free ß-hCG and PAPP-A is influenced by the machine and reagents
used, gestational age, maternal weight, ethnicity, smoking status and method of conception.

In the calculation of accurate patient-specific risks it is necessary to make adjustments in the measured
free ß-hCG and PAPP-A. Each measured level is first converted to a multiple of the expected normal
median (MoM) specific to a pregnancy of the same gestation, maternal weight, smoking status,
ethnicity and method of conception.

In Black women the PAPP-A level is about 60% higher than in White women. Failure to take into
account ethnic origin would result in substantial underestimate of the true risk of trisomy 21 in Black
women. In women who smoke and those conceiving by IVF serum PAPP-A is decreased and this could

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be misinterpreted for increased risk for trisomy 21 and a substantial increase in false positive rates

Reference:

Kagan KO, Wright D, Spencer K, Molina FS, Nicolaides KH. First-trimester screening for trisomy 21 by
free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A: impact of
maternal and pregnancy characteristics. Ultrasound Obstet Gynecol. 2008;31:493-502.

The biochemical markers used in the first trimester ß-hCG and PAPP-A show the following trends in
cases with chromosome abnormalities:

βhCG PAPP-A
T21 ↑ ↓
T18 ↓ ↓
T13 ↓ ↓
Triploidy (paternal) ↑↑↑ ↓
Triploidy (maternal) ↓↓ ↓↓
Sex chromosome abn → ↓

The gestational age used for the calculation of biochemical risk must be derived from the CRL and is
calculated automatically by the software on the basis of the CRL at the time of the 11 – 13 weeks scan
and extrapolated back to the time when the blood was taken if the scan is not performed at the same
time as the blood test.

The program will accept biochemical measurements processed by Brahms Kryptor and Delfia Xpress,
converting these measurements into MoMs. If any other assay system is used, the MoMs rather than
whole values need to be entered, but as the FMF has not certified the laboratory method, it cannot
approve the risk (see the Registered laboratories section of the FMF website www.fetalmedicine.com).
The software user will see a message on the screening saying that Fetal Medicine Foundation has not
approved the biochemical assay used to generate this risk.

Laboratories can manually adjust their medians by 10% if they notice a continuous increase or
decrease of their MoM values.

Recent data suggests that pregnancies with low PAPP-A (<0.3MoMs) should be followed up carefully
because of poor fetal outcome (fetal growth restriction / preterm delivery / fetal death). The FMF
recommends a growth scan at 28 and 32 weeks in addition to their routine antenatal care.

References:
Spencer K, Heath V, El-Sheikhah A, Ong C snd Nicolaides KH. Ethnicity and the need for correction of
biochemical and ultrasound markers of chromosomal anomalies in the first trimester - a study of
Oriental, Asian and Afro-Caribbean populations. Prenat Diagn 20O5:25: 365-369
Kagan K, Frisova V, Nicolaides KH, Spencer K. Dose dependency between cigarette consumption and
reduced maternal serum PAPP-A levels at 11-13+6 weeks of gestation. Prenat Diagn. 2007
Sep;27(9):849-53.

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Spencer K, Bindra R, Nicolaides KH. Maternal weight correction of maternal serum PAPP-A and free
beta-hCG MoM when screening for trisomy 21 in the first trimester of pregnancy. Prenat Diagn. 2003
Oct;23(10):851-5.

Liao A, Heath V, Kametas N, Spencer K, Nicolaides KH. First-trimester screening for trisomy 21 in
singleton pregnancies achieved by assisted reproduction. Hum Reprod. 2001 Jul;16(7):1501-4.

Spencer K, Kagan K, Nicolaides KH. Screening for trisomy 21 in twin pregnancies in the first trimester:
an update of the impact of chorionicity on maternal serum markers. Prenat Diagn. 2008 Jan;28(1):49-
52.

Spencer K, Cowans N, Nicolaides KH. Low levels of maternal serum PAPP-A in the first trimester and
the risk of pre-eclampsia. Prenat Diagn. 2008 Jan;28(1):7-10.

Spencer K, Cowans N, Avgidou K, Molina F, Nicolaides KH. First-trimester biochemical markers of
aneuploidy and the prediction of small-for-gestational age fetuses. Ultrasound Obstet Gynecol. 2008
Jan;31(1):15-9.

Spencer K, Cowans N, Molina F, Kagan K, Nicolaides KH. First-trimester ultrasound and biochemical
markers of aneuploidy and the prediction of preterm or early preterm delivery. Ultrasound Obstet
Gynecol. 2008 Feb;31(2):147-52.

4. MULTIPLE PREGNANCIES

Once a twin pregnancy has been recognised, it is essential that the chorionicity is determined based on
the presence or absence of the lambda sign. The biochemical markers can be included in the risk
calculation but they are affected by chorionicity.

In dating of a multiple pregnancy, the CRL of the largest twin should be used.

In dichorionic twin pregnancies, individual risks will be given for each fetus, based on the findings for
that fetus. In monochorionic twin pregnancies (either mono-amniotic or diamniotic) the average risk will
be displayed for each fetus. A large (>20%) discrepancy between the nuchal translucency
measurements of monochorionic fetuses raises the possibility of early onset severe TTTS.

In multiple pregnancies with more than two fetuses the risk will be based only on ultrasound findings
(NT and other markers).

References:

Spencer K, Nicolaides KH. Screening for trisomy 21 in twins using first trimester ultrasound and
maternal serum biochemistry in a one-stop clinic: a review of three years experience. BJOG. 2003
Mar;110(3):276-80

Vandecruys H, Faiola S, Auer M, Sebire N, Nicolaides KH. Screening for trisomy 21 in monochorionic
twins by measurement of fetal nuchal translucency thickness. Ultrasound Obstet Gynecol. 2005
Jun;25(6):551-3

Kagan K, Gazzoni A, Sepulveda-Gonzalez G, Sotiriadis A, Nicolaides KH. Discordance in nuchal
translucency thickness in the prediction of severe twin-to-twin transfusion syndrome. Ultrasound Obstet
Gynecol. 2007 May;29(5):527-32

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5. RISKS

The T21 risk algorithm is built on the idea of contingent screening:

First-line screening is based on maternal age, fetal NT and serum free ß-hCG & PAPP-A. This will give
high-risk results of more than 1 in 50 or low-risk results of less than 1 in 1000 in about 85% of all
screened pregnancies.

In cases where the first-line screening risk is between 1 in 50 and 1 in 1000 the final risk can be
adjusted by the inclusion of a series of additional ultrasound markers:

• Ductus venosus flow
• Tricuspid flow
• Nasal bone
• Fronto-maxillary-facial angle
• Minor markers

The idea is that these markers need only be taken into account if the risk is equivocal. If the risk after
NT and biochemistry is less than 1:1000, then one abnormal new marker will not increase the risk
significantly and the patient can be classified as low-risk. If the risk is very high after NT and
biochemistry, the risk cannot be improved by the additional markers and the patient is considered as
high-risk. But in the equivocal group, using the additional markers will help to assign them to either a
high or low risk group.

The T21 risk is adjusted by (and in the following order):
• Age & gestation adjusted risk +/- previous history of T21
• NT +/- biochemistry

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• Additional markers Ductus venosus, Tricuspid blood flow, Nose bone
• Facial angle
• Minor markers
• Major defects

The T18 risk is adjusted by (and in the following order):
• Age & gestation adjusted risk +/- previous history of T21
• NT +/- biochemistry
• Additional markers Ductus venosus, Tricuspid blood flow, Nose bone
• Major defects

The T13 risk is adjusted by (and in the following order):
• Age & gestation adjusted risk +/- previous history of T21
• NT +/- biochemistry
• Additional markers Ductus venosus, Tricuspid blood flow, Nose bone
• Fetal heart rate
• Major defects

The software provides the option of giving the risks at the time of the scan or at term.
Depending on the (national) guidelines centres have the option to switch use of new markers on or off.

Truncation limits
Truncation limits have been applied to the likelihood ratio. In addition the risk is capped if the risk falls
outside set limits (1 in 2).

Maximum risk improvement Maximum risk increase
NT alone T21 5x 500x
T18 3x 500x
T13 4x 500x
Biochemistry alone T21, 18 or 13 7x 60x
NT and other USS T21, 18 or 13 20x 1000x
findings
NT and biochemistry T21, 18 or 13 20x 1000x
alone
NT, biochemistry and T21, 18 or 13 33x 1000x
other USS findings

The highest risk that can be given is fixed at 1 in 2.If the risk based on the NT alone is greater than 1 in
100, then the adjusted risk based on the other ultrasound findings too can only be equal to or higher
than the NT only risk. Similarly, if the risk based on the NT and biochemistry is greater than 1 in 50,
then the adjusted risk based on the other ultrasound findings too can only be equal to or higher than
the NT and biochemistry only risk.

Previously affected pregnancy
In women who have had a previous pregnancy with T21, the risk of recurrence in the subsequent
pregnancy is 0.6% higher than the maternal and gestational age-related risk for T21. The possible
mechanism for this increased risk is that a small proportion (less than 5%) of couples with a previously
affected pregnancy have a parental mosaicism or a genetic defect that interferes with the normal
process of dysjunction, so in this group the risk of recurrence is increased substantially. In the majority
of couples (more than 95%), the risk of recurrence is not actually increased. The recurrence is
chromosome-specific.

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Detection rates

5% FPR 2% FPR
NT + biochem 92%
NT + NB, TR, DV, FMF angle + biochem 98% 96%

Risk references:

Robinson HP, Fleming JE. A critical evaluation of sonar "crown-rump length" measurements. Br J
Obstet Gynaecol 1975; 82:702-10
[GAD = 8,052 x (CRL+1)0,5+ 23,73]

Cuckle HE, Wald NJ., Thompson SG. Estimating a woman’s risk of having a pregnancy associated with
Down’s syndrome using her age and
serum alpha-fetoprotein level. Br J Obstet Gynaecol 1987; 94:387-402
[(0.000627+EXP(-16.2395+0.286*AgeEDD)]

Snijders RJM, Sundberg K, Holzgreve W, Henry G,Nicolaides KH. Maternal age and gestation- specific
risk for trisomy 21. Ultrasound Obstet Gynecol 1999;13:167-70.
[Trisomy 21: 10^(0.9425-1.023*LOG10(GAw)+0.2718*(LOG10(GAw))^2)]

Morris JK, Savva GM. The risk of fetal loss following a prenatal diagnosis of trisomy 13 or trisomy 18.
Am J Med Genet A. 2008;1-146:827-32.
[Loss rate trisomy 18 72%, trisomy 13 49%]

Wright D, Kagan KO, Molina FS, Gazzoni A, Nicolaides KH. A mixture model of nuchal translucency
thickness in screening for chromosomal defects. Ultrasound Obstet Gynecol 2008;31:376–383

Kagan O, Wright, Baker A, Sahota D, Nicolaides KH. Screening for trisomy 21 by maternal age, fetal
nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated
plasma protein-A. Ultrasound Obstet Gynecol 2008;31:618-24

Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first-trimester screening
for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-
orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005;25:221-6

Additional Reference list FIRST TRIMESTER SCAN

Wright D, Kagan K, Molina F, Gazzoni A, Nicolaides KH. A mixture model of nuchal translucency
thickness in screening for chromosomal defects. Ultrasound Obstet Gynecol 2008;31:376-83

Snijders R, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk
of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10-14 weeks of gestation.
Fetal Medicine Foundation First Trimester Screening Group. Lancet 19981;352:343-6

Atzei A, Gajewska K, Huggon I, Allan L, Nicolaides KH. Relationship between nuchal translucency
thickness and prevalence of major cardiac defects in fetuses with normal karyotype. Ultrasound Obstet
Gynecol 2005;26:154-7.

Souka A, von Kaisenberg C, Hyett J, Sonek J, Nicolaides KH. Increased nuchal translucency with
normal karyotype. Am J Obstet Gynecol 2005;192:1005-21.

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Cicero S, Avgidou K, Rembouskos G, Kagan K, Nicolaides KH. Nasal bone in first-trimester screening
for trisomy 21. Am J Obstet Gynecol 2006;195:109-14

Falcon O, Faiola S, Huggon I, Allan L, Nicolaides KH. Fetal tricuspid regurgitation at the 11 + 0 to 13 +
6-week scan: association with chromosomal defects and reproducibility of the method. Ultrasound
Obstet Gynecol 2006;27:609-12

Falcon O, Auer M, Gerovassili A, Spencer K, Nicolaides KH. Screening for trisomy 21 by fetal tricuspid
regurgitation, nuchal translucency and maternal serum free beta-hCG and PAPP-A at 11 + 0 to 13 + 6
weeks. Ultrasound Obstet Gynecol 2006;27:151-5

Matias, A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities
at 10-14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol 1998;12:380-4

Borenstein M, Persico N, Kaihura C, Sonek J, Nicolaides KH. Frontomaxillary facial angle in
chromosomally normal fetuses at 11+ 0 to 13+ 6 weeks. Ultrasound Obstet Gynecol 2007;30:737–741
Sonek J, Borenstein M, Dagklis T, et al. Frontomaxillary facial angle in fetuses with trisomy 21 at 11+ 0
to 13+ 6 weeks. Am J Obstet Gynecol 2007;196;271.e1-4

Sonek J, Borenstein M, Downing C et al. Frontomaxillary facial angles in screening for trisomy 21 at 14-
23 weeks' gestation. Am J Obstet Gynecol 2007;197:160.e1-5

Dagklis T, Plasencia W, Maiz N, Duarte L, Nicolaides KH. Choroid plexus cyst, intracardiac echogenic
focus, hyperechogenic bowel and hydronephrosis in screening for trisomy 21 at 11 + 0 to 13 + 6 weeks.
Ultrasound Obstet Gynecol 2008;31:132-5

Liao A, Sebire N, Geerts L, Cicero C, Nicolaides KH. Megacystis at 10-14 weeks of gestation:
chromosomal defects and outcome according to bladder length. Ultrasound Obstet Gynecol
2003;21:338-41

Reference list OBSTETRIC RISKS IN FIRST TRIMESTER OF PREGNANCY (Preeclampsia, Fetal
Growth restriction, Fetal Death)

Plasencia W, Maiz N, Bonino S, Kaihura C, Nicolaides KH. Uterine artery Doppler at 11+ 0 to 13+ 6
weeks in the prediction of pre-eclampsia. Ultrasound Obstet Gynecol 2007;30:742-9.

Poon L, Maiz N, Valencia C, Plasencia W, Nicolaides KH. First trimester maternal serum PAPP-A and
pre-eclampsia. Ultrasound Obstet Gynecol 2009;33:23-33

Khaw A, Kametas N, Turan O, Bamfo J, Nicolaides KH. Maternal cardiac function and uterine artery
Doppler at 11-14 weeks in the prediction of pre-eclampsia in nulliparous women. BJOG. 2008;115:369-
76

Spencer K, Cowans NJ, Avgidou K, Molina F, Nicolaides KH. First-trimester biochemical markers of
aneuploidy and the prediction of small-for-gestational age fetuses. Ultrasound Obstet Gynecol.
2008;31:15-9

Maiz, N, Valencia, C, Emmanuel, EE, Staboulidou, I, Nicolaides, KH.Screening for adverse pregnancy
outcome by Ductus venosus Doppler at 11-13+6 weeks. Obstet Gynecol 2008;112:598–605

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6. RISKS FOR HYPERTENSIVE DISORDERS
1. There are three end points:
• Gestational hypertension
• Early preeclampsia (requiring delivery before 34 weeks)
• Late preeclampsia (delivery at or after 34 weeks)
2. Prediction of the three end points is provided by maternal risk factors. This gives the a priori or
background risk (like maternal age and gestation in trisomy 21)
3. The maternal factor a priori risk is modified by:
• Uterine artery PI (L-PI; taken from the measurement of the vessel with the lowest PI)
• Mean arterial pressure (MAP)
• The combination of uterine artery L-PI and MAP
• Serum PAPP-A or serum PlGF. If both PAPP-A and PlGF are measured then PAPP-A
does not remain in the final model
• The combination of uterine artery L-PI, MAP and biochemistry
4. The questions for the maternal risk factors are all compulsory

The following results are then presented:

1. Risk for early-PE
2. Risk for PE at any gestation (ealy-PE plus late-PE)
3. Risk for all hypertensive disorders (early-PE plus late-PE plus GH)

References:

Poon LCY, Kametas NA, Chelemen T, Leal A, Nicolaides KH. Maternal risk factors for hypertensive
disorders in pregnancy: a multivariate approach. J Hum Hypertens 2009 Jun 11. [Epub ahead of print]

Poon LCY, Staboulidou I, Maiz N, Plasencia W, Nicolaides KH. Hypertensive disorders in pregnancy:
screening by uterine artery Doppler at 11-13 weeks. Ultrasound Obstet Gynecol, in press.

Poon LCY, Kametas NA, Valencia C, Chelemen T, Nicolaides KH. Hypertensive disorders in
pregnancy: screening by systolic diastolic and mean arterial pressure at 11-13 weeks. J Hypertens, in
press.

Poon LCY, Karagiannis G, Leal A, Romero Infante X, Nicolaides KH. Hypertensive disorders in
pregnancy: screening by uterine artery Doppler and blood pressure at 11-13 weeks. Ultrasound Obstet
Gynecol, in press.

For the latest information, please see on the Fetal Medicine Foundation website
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

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DOPPLER

Mean Arterial Pressure (MAP)

There are two ways to calculate the MAP. You can use either method in this software.

1. If the machine does not give MAP but systolic (sBP) and diastolic pressure (dBP): record two
measurements of sBP and dBP for the left arm and two for the right. The software will calculate
from each set of measurements the MAP (MAP = dBP + (sBP – dBP) / 3) . It will take the
average MAP of the left arm and the average MAP of the right arm and use the highest of the
two averages for further calculations
2. If the machine gives the MAP: record two measurements for the left arm and two for the right.
The software will take the average MAP of the left arm and the average MAP of the right arm
and use the highest of the two averages for further calculations

For the purposes of risk calculation for hypertensive disorders, the MAP is converted to a multiple of
the median (MoM). This is displayed, provided all the required factors are entered. These are:

• Ethnicity
• Body-mass index
• CRL
• Maternal age
• Smoking status

For the latest information, please see on the Fetal Medicine Foundation website

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(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

Uterine artery Doppler

The uterine artery pulsatility index (PI) at 11-13 weeks is increased in pregnancies that subsequently
develop preeclampsia (PE), and the increase is particularly marked for early-PE.
The performance of screening with the lowest PI appears to be the best when compared to the mean
PI of the two uterine arteries and the highest PI.

Reference:
Hypertensive disorders in pregnancy: Screening by uterine artery Doppler at 11-13 weeks . Poon LCY,
Staboulidou S, Maiz N, Plasencia W, Nicolaides KH. Ultrasound Obstet Gynecol 2009; in press

PlGF

The measurement of maternal serum placental growth factor in combination with maternal history, plus
uterine artery pulsatility index and mean arterial pressure provides the highest detection rate for early
and late preclampsia, as shown here:

Screening test Early preeclampsia Late preeclampsia Gestational
hypertension
Detection rate (%) for fixed false positive rate (95% CI)
5% 10% 5% 10% 5% 10%
PlGF and maternal 76.9 88.5 41.8 59.3 43.5 49.4
factors plus MAP
Uterine artery L-PI 76.9 76.9 38.5 53.8 - -
MAP, Uterine artery L- 92.3 92.3 50.5 64.8 - -
PI

For the purposes of risk calculation for hypertensive disorders, the PlGF value is converted to a
multiple of the median (MoM). This is displayed, provided all the required factors are entered in the
PET screen. These are:

• Ethnicity
• Maternal weight
• CRL
• Smoking status

Reference:

Poon LCY; Kametas NA; Maiz N; Akolekar R; Nicolaides KH. First-Trimester Prediction of Hypertensive
Disorders in Pregnancy. Hypertension. 2009;53:812-8

For the latest information, please see on the Fetal Medicine Foundation website
(http://www.fetalmedicine.com/fmf/online-education/01-11-136-week-scan/).

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Screening for preeclampsia

Preeclampsia (PE), which affects about 2% of pregnancies, is a major cause of perinatal and maternal
morbidity and mortality. It is early-PE requiring delivery before 34 weeks rather than late PE which is
associated with an increased risk of perinatal mortality and morbidity and both short-term and long-term
maternal complications. Identification of women at high-risk for PE could potentially improve pregnancy
outcome because intensive maternal and fetal monitoring in such patients would lead to an earlier
diagnosis of the clinical signs of the disease and the associated fetal growth restriction and avoid the
development of serious complications through such interventions as the administration of
antihypertensive medication and early delivery
The a priori risk for preeclampsia is based on the prevalence of this condition, 2% for all preeclampsia
and 0.5% for early preeclampsia.
The patient-specific risk of developing PE can be predicted by a combination of factors in the maternal
history, including Black racial origin, high body mass index and prior or family history of PE, and the
following measurements taken at 11-13 weeks:
• maternal blood pressure
• uterine artery pulsatility index (PI)
• maternal serum level of PAPP-A
• maternal serum level of PLGF

Screening by this combined approach could identify about 90% and 45% of patients developing early-
PE and late-PE, respectively, at a false positive rate of 5%.

Screening for preeclampsia can also be achieved by a combination of maternal history with any one of
these markers above.

Detection rate (%) for fixed false positive rate
Screening test Early preeclampsia Late preeclampsia Gestational hypertension
5% 10% 5% 10% 5% 10%
Maternal factor 37.0 47.0 28.9 41.4 20.7 30.7
Maternal factor plus
Uterine artery L-PI 64.9 81.1 32.0 45.3 17.9 35.0
MAP 48.6 75.7 39.8 52.3 36.4 47.9
PAPP-A 45.9 59.5 31.7 45.2 - -
PlGF 53.8 65.4 38.9 46.7 - -
Uterine artery L-PI, MAP 78.4 89.2 42.2 57.0 35.7 50.0
Uterine artery L-PI, PAPP-A 67.6 81.1 - - - -
Uterine artery L-PI, PlGF 76.9 76.9 36.7 51.1 - -
MAP, PAPP-A 64.9 73.0 38.9 52.4 - -
MAP, PlGF 76.9 88.5 41.1 57.8 - -
Uterine artery L-PI, MAP, PAPP- 83.8 94.6 - - - -
A
Uterine artery L-PI, MAP, PlGF 88.5 92.3 38.9 64.4 - -

Reference:
Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive
disorders in pregnancy. Hypertension. 2009;53:812-8.

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7. SCREENING FOR FETAL DEATH

Reversed a-wave in the ductus venosus is seen in approximately 4% of fetuses at 11+ 0 to 13+ 6
weeks and it is well documented that this abnormal flow pattern is associated with increased risk of
chromosomal abnormalities, fetal cardiac defects and fetal death. In the euploid fetus in the second and
third trimesters of pregnancy it is well documented that abnormal flow in the ductus is associated with
fetal compromise and this appears to be also true in the first trimester. However, in about 80% of cases
with a reversed a-wave the pregnancy outcome will be normal.

The flow through the ductus venosus should be observed and documented as either normal or
reversed. This finding can then be combined with the other factors providing a significant contribution to
the risk of fetal death in a euploid fetus, including:

• Maternal ethnic group (risk of fetal death is higher in Black mothers)
• Maternal BMI (risk of fetal death increases with increasing BMI)
• NT measurement at 11+ 0 to 13+ 6 weeks (risk of fetal death increases with increasing NT)
• PAPP-A measurement at 11+ 0 to 13+ 6 weeks (risk of fetal death is higher with a low PAPP-A)

The FMF software will use these factors to calculate a risk of fetal death. However it is essential that all
the necessary demographic fields are accurately completed and that the FMF guidelines for the
assessment of the DV are followed correctly. The risk of fetal death will only be taken into account if the
required fields completed and you hold the FMF certificate of competence in the measurement of NT
and DV assessment and have both included in your license.

Reference:

Maiz N,, Valencia C, Emmanuel W, Staboulidou I, Nicoliades KH. Screening for adverse pregnancy
outcome by Ductus venosus Doppler at 11 to 13+ 6 weeks. Obstet Gynecol 2008;112:598-605.

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8. 2ND TRIMESTER RISK ASSESSMENT

Minor abnormalities:

Minor fetal abnormalities or soft markers are common and they are not usually associated with any
handicap, unless there is an underlying chromosomal defect.

• Invasive testing of all pregnancies with these markers would have major implications, both in
terms of miscarriage and in economic costs. It is best to base counseling on an individual
estimated risk for a chromosomal defect, rather than the arbitrary advice that invasive testing is
recommended because the risk is 'high'
• The estimated risk can be derived by multiplying the a priori risk (based on the results of
previous combined screening by maternal age, fetal NT, FHR and serum free ß-hCG and
PAPP-A) by the likelihood ratio of the specific abnormality or marker.
• For isolated abnormalities the likelihood ratio for trisomy 21 is:
• About 1 (therefore the a priori risk is not increased) in the case of choroid plexus cysts,
echogenic endocardiac focii, mild hydronephrosis and short femur
• About 10 (therefore there is a 10-fold increase in the a priori risk) for nuchal or prenasal
edema and hypoplastic nasal bone

The absence of second trimester US markers

The absence of any major or minor defect in the second trimester scan is associated with a reduction in
the background risk. The a priori risk is the age-based risk if the mother had no previous screening, and
the calculated individual risk derived from the previous screening test if she had a screening test before
The likelihood ratio for trisomy 21 if there is no detectable defect or marker is 0.30. There are some

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exceptions to this process of sequential screening, which assumes independence between the findings
of different screening results. The findings of nuchal edema at the mid-trimester scan cannot be
considered independently of NT screenin at 11-14 weeks. Therefore, in patients who had a previous
NT scan, the likelihood ratio for trisomy 21 in the absence of detectable makers is about 0.20.

Reference:

Nicolaides KH. Screening for chromosomal defects (editorial). Ultrasound Obstet Gynecol 2003.
21:313-321.

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Appendix 1
Protocol for the measurement of nuchal translucency

• The gestational period must be 11 to 13 weeks and six days.
• The fetal crown-rump length should be between 45 and 84mm.
• The magnification of the image should be such that the fetal head and thorax occupy the
whole screen.
• A mid-sagittal view of the face should be obtained. This is defined by the presence of the
echogenic tip of the nose and rectangular shape of the palate anteriorly, the translucent
diencephalon in the centre and the nuchal membrane posteriorly. Minor deviations from the
exact midline plane would cause non-visualization of the tip of the nose and visibility of the
zygomatic process of the maxilla.
• The fetus should be in a neutral position, with the head in line with the spine. When the fetal
neck is hyperextended the measurement can be falsely increased and when the neck is
flexed, the measurement can be falsely decreased.
• Care must be taken to distinguish between fetal skin and amnion.
• The widest part of translucency must always be measured.
• Measurements should be taken with the inner border of the horizontal line of the callipers
placed ON the line that defines the nuchal translucency thickness - the crossbar of the
calliper should be such that it is hardly visible as it merges with the white line of the border,
not in the nuchal fluid.
• In magnifying the image (pre or post freeze zoom) it is important to turn the gain down. This
avoids the mistake of placing the calliper on the fuzzy edge of the line which causes an
underestimate of the nuchal measurement.
• During the scan more than one measurement must be taken and the maximum one that
meets all the above criteria should be recorded in the database.
• The umbilical cord may be round the fetal neck in about 5% of cases and this finding may
produce a falsely increased NT. In such cases, the measurements of NT above and below
the cord are different and, in the calculation of risk, it is more appropriate to use the average
of the two measurements

Quality review and ongoing Certification in nuchal translucency
• Each sonographer must submit NT data and 3 images for audit 12 months after obtaining
the FMF Certificate of competence in NT and the FMF software for the calculation of risks. In
addition to the FMF audit, all sonographers are encouraged to perform their own internal
quality assurance on a monthly basis by examining their NT distribution using the automated
audit module incorporated within the FMF risk calculation software.
• The audit involves assessment of the distribution of NT measurements of each sonographer
and examination of their images. Sonographers passing their audit will be re-audited and re-
licensed on an annual basis thereafter. The NT distribution cannot be assessed if fewer than
30 scans have been performed, but in this situation an individual can still pass their audit if
their images are satisfactory.
• If the NT distribution falls outside the satisfactory range advice will be given on how to
improve the NT technique, based on the review of images. The name of the sonographer will
be removed from the FMF website list of holders of the Certificate of competence in NT. A
new audit will be carried out in 3 months (please see audit policies on your own FMF page)
and the sonographer will only be reinstated on the FMF website list once the audit is
considered satisfactory. However, if in the new audit the standard of the sonographer has not
improved then their FMF software license will be revoked. In such case the sonographer will
need to be retrained and apply for recertification by attending the FMFinternet based course
on the 11-13 weeks scan and submitting the appropriate logbook of images.

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Requirements for Certification in the measurement of nuchal translucency
The requirements for certification are:
1. Attendance of the internet based course on the 11-13 weeks scan. This course is intended for
all medical personnel involved in antenatal care and is not confined to those performing the 11-
13 weeks scan.
2. Submission of a logbook of 3 images demonstrating the measurement of NT.

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Appendix 2
Protocol for the assessment of fetal nasal bone

• The gestational period must be 11 to 13 weeks and six days.
• The magnification of the image should be such that the fetal head and thorax occupy the
whole image.
• A mid-sagittal view of the face should be obtained. This is defined by the presence of the
echogenic tip of the nose and rectangular shape of the palate anteriorly, the translucent
diencephalon in the centre and the nuchal membrane posteriorly. Minor deviations from the
exact midline plane would cause non-visualization of the tip of the nose and visibility of the
zygomatic process of the maxilla.
• The ultrasound transducer should be held parallel to the direction of the nose and should be
gently tilted from side to side to ensure that the nasal bone is seen separate from the nasal
skin.
• The echogenicity of the nasal bone should be greater that the skin overlying it. In this
respect, the correct view of the nasal bone should demonstrate three distinct lines: the first
two lines, which are proximal to the forehead, are horizontal and parallel to each other,
resembling an "equal sign". The top line represents the skin and bottom one, which is thicker
and more echogenic than the overlying skin, represents the nasal bone. A third line, almost
in continuity with the skin, but at a higher level, represents the tip of the nose.
• When the nasal bone line appears as a thin line, less echogenic than the overlying skin, it
suggests that the nasal bone is not yet ossified, and it is therefore classified as being absent.

Clinical application of findings from assessment of the nasal bone
The incidence of an absent nasal bone is related to NT, CRL and ethnic origin as well as aneuploidy,
being more common when the NT is high, the CRL is low and the mother is Black. Therefore, it is not
possible to give simple numbers by which the presence of the nasal bone will reduce the risk for
trisomy 21 and the absence will increase the risk.
The FMF software firstly calculates a risk based on maternal age, fetal NT and maternal serum free β-
hCG and PAPP-A. If the risk is more than 1 in 50 and and the nasal bone is normal the risk does not
change. If the risk is 1 in 50 to 1 in 1,000 and the nasal bone is normal the risk is usually reduced. If
the nasal bone is absent the risk is always increased. The difficulty is when the gestation is 11 weeks
or the beginning of the 12th week and the nasal bone is absent but the NT, the other ultrasound
markers and the serum biochemistry are normal. In this cases our advice is that the patients are
rescanned in one week and action is only taken at that point if there is persistence of the absence of
the nasal bone.

Requirement for Certification in assessment of the nasal bone
The requirements for certification are:
1. FMF certification in measurement of nuchal translucency.
2. Attendance of the internet based course on the 11-13 weeks scan.
3. Submission of a logbook of 3 images including two with normal and one with absent nasal bone
at 11-13 weeks.

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Appendix 3
Protocol for the assessment of fetal tricuspid flow

• The gestational period must be 11 to 13 weeks and six days.
• The magnification of the image should be such that the fetal thorax occupies most of the
image.
• An apical four-chamber view of the fetal heart should be obtained.
• A pulsed-wave Doppler sample volume of 2.0 to 3.0 mm should be positioned across the
tricuspid valve so that the angle to the direction of flow is less than 30 degrees from the
direction of the inter-ventricular septum.
• Tricuspid regurgitation is diagnosed if it is found during at least half of the systole and with a
velocity of over 60 cm/s, since aortic or pulmonary arterial blood flow at this gestation can
produce a maximum velocity of 50 cm/s.
• The tricuspid valve could be insufficient in one or more of its three cusps, and therefore the
sample volume should be placed across the valve at least three times, in an attempt to
interrogate the complete valve.

Clinical application of tricuspid flow findings
The incidence of tricuspid regurgitation is related to NT and CRL as well as aneuploidy, being more
common when the NT is high and the CRL is low. Therefore it is not possible to give simple numbers
by which the presence of normal flow will reduce the risk for trisomy 21 and the presence of tricuspid
regurgitation will increase the risk.
The FMF software firstly calculates a risk based on maternal age, fetal NT and maternal serum free β-
hCG and PAPP-A. If the risk is more than 1 in 50 and tricuspid flow is normal the risk does not
change. If the risk is 1 in 50 to 1 in 1,000 and the tricuspid flow is normal the risk is usually reduced. If
there is tricuspid regurgitation the risk is always increased. In addition, there is an increased risk for
cardiac defects and therefore such patients should have a follow up specialist fetal cardiac scan.

Requirements for Certification in assessment of tricuspid flow
The requirements for certification are:
1. FMF certification in measurement of nuchal translucency.
2. Attendance of the internet based course on the 11-13 weeks scan.
3. Submission of a logbook of 3 images including two with normal flow and one with tricuspid
regurgitation at 11-13 weeks.

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Appendix 4

Protocol for the assessment of the ductus venosus

• The gestational period must be 11 to 13 weeks and six days.
• The examination should be undertaken during fetal quiescence.
• The magnification of the image should be such that the fetal thorax and abdomen occupy the
whole image.
• A right ventral mid-sagittal view of the fetal trunk should be obtained and color flow mapping
should be undertaken to demonstrate the umbilical vein, ductus venosus and fetal heart.
• The pulsed Doppler sample volume should be small (0.5 mm) to avoid contamination from
the adjacent veins, and it should be placed in the yellowish aliasing area.
• The insonation angle should be less than 30 degrees.
• The filter should be set at a low frequency (50-70 Hz) so that the a-wave is not obscured.
• The sweep speed should be high (2-3 cm/s) so that the waveforms are spread allowing
better assessment of the a-wave.
• When these criteria are satisfied, it is possible to assess the a-wave and determine
qualitatively whether the flow is positive, absent or reversed.

Clinical application of ductus venosus flow findings
The incidence of reversed ductus venosus a-wave is related to NT and CRL as well as aneuploidy,
being more common when the NT is high and the CRL is low. Therefore it is not possible to give
simple numbers by which the presence of normal flow will reduce the risk for trisomy 21 and the
presence of reversed a-wave will increase the risk.
The FMF software firstly calculates a risk based on maternal age, fetal NT and maternal serum free β-
hCG and PAPP-A. If the risk is more than 1 in 50 and ductus venosus flow is normal the risk does not
change. If the risk is 1 in 50 to 1 in 1,000 and the ductus venosus flow is normal the risk is usually
reduced. If there is reversed a-wave the risk is always increased. In addition, there is an increased risk
for cardiac defects and therefore such patients should have a follow up specialist fetal cardiac scan.

Requirements for Certification in assessment of ductus venosus flow
The requirements for certification are:
1. FMF certification in measurement of nuchal translucency.
2. Attendance of the internet based course on the 11-13 weeks scan.
3. Submission of a logbook of 3 images including two with positive and one with reversed a-wave
at 11-13 weeks.

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The Fetal Medicine Foundation

Appendix 5
Protocol for the measurement of the facial angle

• The gestational period must be 11 to 13 weeks and six days.
• The magnification of the image should be such that the fetal head and thorax occupy the
whole image.
• A mid-sagittal view of the face should be obtained. This is defined by the presence of the
echogenic tip of the nose and rectangular shape of the palate anteriorly, the translucent
diencephalon in the centre and the nuchal membrane posteriorly. Minor deviations from the
exact midline plane would cause non-visualization of the tip of the nose and visibility of the
zygomatic process of the maxilla.
• The facial angle should be measured between a line along the upper surface of the palate
and a line which traverses the upper corner of the anterior aspect of the maxilla extending to
the external surface of the forehead, represented by the frontal bones or an echogenic line
under the skin below the metopic suture that remains open.

Clinical application of fetal facial angle measurement
The fetal facial angle decreases with CRL and is wider in fetuses with trisomy 21 than in
chromosomaly normal fetuses. It is essential that in adjusting the risk for trisomy 21 using the
measurement of the facial angle the software takes into account the fetal CRL.
The FMF software firstly calculates a risk based on maternal age, fetal NT and maternal serum free β-
hCG and PAPP-A. If the risk is more than 1 in 50 and and the facial angle is within the normal range
the risk does not change. If the risk is 1 in 50 to 1 in 1,000 and the the facial angle is within the normal
range the risk is usually reduced. If the facial angle is above the bormal range the risk is always
increased.

Requirements for Certification in measurement of the facial angle
The requirements for certification are:
1. FMF certification in measurement of nuchal translucency.
2. Attendance of the internet based course on the 11-13 weeks scan.
3. Submission of a logbook of 3 images demonstrating the measurement of the facial angle at 11-
13 weeks.

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The Fetal Medicine Foundation

Appendix 6

Protocol for the first-trimester assessment of uterine artery Doppler

• The gestational age must be between 11 weeks and 13 weeks and six days.
• Sagittal section of the uterus must be obtained and the cervical canal and internal cervical os
identified. Subsequently, the transducer must be gently tilted from side to side and then
colour flow mapping should be used to identify each uterine artery along the side of the
cervix and uterus at the level of the internal os.
• Pulsed wave Doppler should be used with the sampling gate set at 2 mm to cover the whole
vessel and ensuring that the angle of insonation is less than 30º. When three similar
consecutive waveforms are obtained the PI must be measured and the mean PI of the left
and right arteries be calculated.

Requirements for Certification in measurement of uterine artery PI
The requirements for certification are:
1. FMF certification in the measurement of nuchal translucency.
2. Attendance of the internet based course on the 11-13 weeks scan.
3. Submission of a logbook of 3 images demonstrating color flow mapping and waveforms of the
uterine artery at 11-13 weeks.

For the latest information, please see on the Fetal Medicine Foundation website.

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