03 Guide for the First Trimester Screening Module

The Fetal Medicine Foundation

The First Trimester Screening module 2012 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).

Overview of changes

The Fetal Medicine Foundation has released an improved 1st Trimester algorithm (FMF 2012). There are no changes to risk calculation by nuchal translucency and most other ultrasound markers.

The new software has incorporated the latest research publications to allow calculation of risks for preeclampsia and fetal growth restriction 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 and pregnancy characteristics, uterine artery Doppler (mean PI), mean arterial pressure (MAP), PAPP-A and PlGF. Risks are calculated for early preeclampsia (before 34 weeks), for preeclampsia before 37 weeks, for all preeclampsia and for fetal growth restriction before 37 weeks. The detection rates and false positive rates for each combination are available in the program help pages.

There is a new algorithm for the risk of spontaneous preterm delivery before 34 weeks using maternal history and first trimester cervical length.

There have also been several improvements in the algorithm for the calculation of risks for aneuploidies. Ductus venosus PI has replaced the normal/abnormal assessment of ductus venosus; biochemical MoMs now include gestational age–related factors and new factors for diabetes mellitus; PlGF is added as a marker for trisomies; MoMs from a previous normal pregnancy can be used to adjust for patient-specific levels of markers.

Facial angle and the 'minor markers' have been removed from the algorithm. Also removed is the built-in 'contingent' policy which meant that risks based on NT and biochemistry would not be reduced by other ultrasound markers when the risk was high.

Another important function of the software is the ability of individual centres to monitor their median values of free ß-hCG, PAPP-A and PlGF and adjust the values themselves. An adjustment of between 0.5 to 1.5 on individual MoMs can be made; this can be calculated from the past year's data, provided at least 100 cases have been analysed in the last six months.

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http://www.fetalmedicine.com/fmf/training-certification/certificates-of-competence/the-11-136-week-scan/

http://www.fetalmedicine.com/fmf/training-certification/certificates-of-competence/the-11-136-week-scan/

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


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 their setting to reflect this, as otherwise an increased false-positive rate will result. An adjustable risk cutoff of 1:50 for trisomy 18+13 has been implemented. Risk cutoffs for preeclampsia and FGR are implemented internally to provide a screen-positive rate of 10% irrespective of the method of screening.

The audit module has been enhanced to include distributions for PlGF, uterine artery PI, ductus venosus PI and MAP. Distribution plots for ultrasound markers include N (number of observations), mean (mean log10 MoM) and standard deviation, indicating in red type where any of these fail to meet FMF standards for (re-)certification.

Before starting to use the FTS software, please ensure that you have imported or downloaded your FMF software license. Although it is possible to explore the data screens without a valid operator, it will not be possible to save patient data without specifying a valid operator.

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1. FIRST TRIMESTER HISTORY

All maternal history and pregnancy characteristics are grouped in this screen.

Items with green labels are required for risk calculations: for calculation of risks for aneuploidies only, the required fields are racial origin, parity, weight, smoking, diabetes mellitus and method of conception.

Some fields are only displayed when parity is not zero.

Racial origin

The prevalence of abnormal findings in ultrasound markers (nasal bone, ductus venosus, tricuspid flow, uterine artery PI) varies with the racial origin of the mother. In addition, maternal racial origin has a major influence on maternal serum biochemistry. Therefore, it is important to accurately record the racial origin 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)

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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 Mar;33(3):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

For the purpose of risk estimation for either aneuploidies or pregnancy complications there are essentially two methods of assisted conception.

1.In vitro fertilization (IVF), which includes ICSI, irrespective of the source of the eggs or sperms.2.Ovulation induction drugs without IVF, which includes Clomifene or other drugs and either sexual intercourse or artificial insemination of sperms from any source.

For the purpose of this program, conception by artificial insemination of sperms from any source without the use of ovulation drugs should be classified as 'spontaneous'.

In the case of IVF pregnancies, irrespective of the source of fresh eggs, you should record the date of fertilization, which is essentially the date of egg collection, rather than the date of embryo transfer because this may vary by several days. The software will automatically calculate the LMP as the date of fertilization minus 14 days

In the case of using frozen embryos, you should record the date of embryo transfer. The software will assume that freezing occurred on the 3rd day after fertilization and will estimate the LMP as being 17 days before embryo transfer.

With regard to maternal age, it is important to know whether the cycle used the mother's own eggs, or those of a donor and whether the eggs were frozen and, if so, for how long. The program allows you to 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 for aneuploidies 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.

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It should be noted that in the calculation of risks for aneuploidies and pregnancy complications all biochemical and biophysical markers are expressed as multiples of the median corrected for the measured crown-rump length rather than gestational age as calculated by the software.

Birthweight calculator

To fill the field 'Previous small baby', a calculator is provided as a button which invokes a small dialog. The birthweight and gestational age at delivery of any previous pregnancy can be entered. If the values are in range (GA between 20 - 44 weeks and weight between 200 - 8000g) a z-score is calculated. If the score is less than -1.645 (below the 5th centile), the message 'Below the 5th centile (SGA)' is displayed. If the score is above, the message 'Above the 5th centile (non-SGA)' appears instead.

Pressing the Apply button transfers the results to the 'Previous small baby' field (in terms of yes, no).

Reference

Poon LC, Volpe N, Muto B, Syngelaki A, Nicolaides KH. Birthweight with gestation and maternal characteristics in live births and stillbirths. Fetal Diagn Ther. 2012. Pub online 2012 July 26.

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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.

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

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.

After numerous changes to the algorithm in earlier versions of the software, since version 2.0 the mixture model of NT distributions has been established. 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.

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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 calculation of the average NT once the two NT values are correctly entered when prompted.

Ductus venosus

Effective first-trimester screening for trisomy 21 is provided by a combination of maternal age, fetal NT thickness and maternal serum free ß-hCG and PAPP-A, with an estimated detection rate (DR) of about 90% at a false-positive rate (FPR) of 3%. A new study demonstrates that incorporating measurement of ductus venosus PIV in first-trimester combined screening can improve the DR to about 95% and reduce the FPR to about 2.5%. Alternatively, combining fetal NT with DV PIV alone has essentially the same high performance as screening by a combination of fetal NT with serum biochemistry.

Risk assessment by ductus venosus PI is similar to nuchal translucency, in that the distributions in trisomies and unaffected populations are best described by a mixture model, with CRL-dependent and CRL-independent distributions.

Sonographers undertaking risk assessment by Doppler examination of the DV should receive appropriate training and certification of their competence in performing such a scan and should adhere to a series of strict criteria for obtaining the appropriate waveform. It has been shown that sonographers with prior extensive experience in the 11-13 weeks scan require an average of 80 examinations before they could achieve this level of competence.


Reference:

Maiz N, Wright D, Ferreira AFA, Syngelaki A, Nicolaides KH. A mixture model of ductus venosus pulsatility index in screening for aneuploidies at 11-13 weeks' gestation. Fetal Diagn Ther. 2012; 31:221-229.

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 racial origin, so it is important to correctly enter maternal racial origin. The software will not use the fetal nasal bone in the risk calculation if the racial origin is not entered using the groupings 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

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you hold the FMF certificate of competence in NB have the NB included in your license.


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 Mar;33(3):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.

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


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 Jan;33(1):18-22

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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 riskT21 T18 T13

Holoprosencephaly - - 1 in 2Diaphragmatic hernia - 1 in 4 -AVSD 1 in 2 - -Exomphalos - 1 in 4 1 in 10Megacystis - 1 in 10 1 in 10Exomphalos and megacystis - 1 in 3 1 in 3Holoprosencephaly 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.

ExomphalosA 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.

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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.

Diaphragmatic herni a 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 intra-thoracic herniation of the abdominal viscera in the first trimester and prolonged compression of the lungs causes pulmonary hypoplasia.

Reference:

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

Kagan KO, Staboulidou I, Syngelaki A, Cruz J, Nicolaides KH. The 11-13-week scan: diagnosis and outcome of holoprosencephaly, exomphalos and megacystis. Ultrasound Obstet Gynecol 2010;36:10-4

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3. MATERNAL SERUM BIOCHEMISTRY

MoMs (multiples 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. Note that while the concentration and MoM of AFP can both be recorded, this biochemical marker is not used in the risk calculation.

Important: MoMs will only be calculated if all of the relevant factors are entered

• Date of blood sample• Gestational age (based on a CRL between 45-84 mm)• Maternal weight (in kg)• Racial origin• Smoking (yes / no)• Method of conception• Diabetes mellitus• Parity (nulliparous / parous)• Number of fetuses (automatically recorded)• Equipment (Brahms Kryptor, Delfia Xpress or Roche)• Chorionicity in the case of twins

Biochemistry MoMsThe measured concentrations of free ß-hCG, PAPP-A and PlGF are influenced by the machine and reagents used, and all factors listed above.

In the calculation of accurate patient-specific risks it is necessary to make adjustments in the measured free ß-hCG, PAPP-A and PlGF. 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, racial origin and method of conception.

In Black women the PAPP-A level is about 60% higher than in White women. Failure to take into account racial origin would result in substantial underestimate of the true risk of

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trisomy 21 in Black women. In women who smoke and those conceiving by IVF serum PAPP-A is decreased and this could be misinterpreted for increased risk for trisomy 21 and a substantial increase in false positive rates.

A new feature in this software version is the use of factors which vary according to the gestational age at blood sampling. This applies to factors for racial origin, method of conception and smoking.

Another new feature is the ability to enter MoMs from a previous normal pregnancy. There is a correlation between a patient's MoMs in different pregnancies, meaning that for example, a woman with high free ß-hCG and low PAPP-A, who delivers a chromosomally normal baby may have the same 'abnormal' biochemistry in a subsequent pregnancy. By entering the previous MoM values, we can calculate patient-specific distributions which will prevent her risk from being increased unnecessarily. Currently, only previous MoMs for free ß-hCG and PAPP-A are used.

Roche medians, which were introduced in the previous software version, are now available for the full range of gestational age (8 – 14 weeks).

Reference s :

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.

Pandya P, Wright D, Syngelaki A, Akolelar R, Nicolaides KH. Maternal Serum Placental Growth Factor in Prospective Screening for Aneuploidies at 8-13 Week's Gestation. Fetal Diagn Ther. 2012;31(2):87-93. Epub 2012 Jan 27.

Ball S, Ekelund C, Wright D, Kirkegaard I, Nørgaard P, Petersen O, Tabor A. Temporal effects of maternal and pregnancy characteristics on serum PAPP-A and free β-hCG at 7-14 weeks’ gestation. Ultrasound Obstet Gynecol 2012 (accepted for publication – accepted online: 11 Jun 2012)

Ball S, Wright D, Sodre D, Lachmann R, Nicolaides KH. Temporal effect of Afro Caribbean race on serum PAPP-A at 9-13 weeks’ gestation in screening for aneuploidies.Fetal Diagn Ther. 2012;31(3):162-9. Epub 2012 Feb 25.

Wright D, Syngelaki A, Birdir C, Bedei I, Nicolaides KH. First-Trimester Screening for Trisomy 21 with Adjustment for Biochemical Results of Previous Pregnancies. Fetal Diagn Ther. 2011; 30: 194-202.

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

ß-hCG PAPP-A

T21 ↑ ↓

T18 ↓ ↓

T13 ↓ ↓

Triploidy (paternal) ↑↑↑ ↓

Triploidy (maternal) ↓↓ ↓↓

Sex chromosome abnormality

↓

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, Delfia XPress or Roche, 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 50% 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 and 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: 365-369Kagan K, Frisova V, Nicolaides KH, Spencer K. Dose dependency between cigarette con-sumption and reduced maternal serum PAPP-A levels at 11-13+6 weeks of gestation. Prenat Diagn. 2007 Sep;27(9):849-53.

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.

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http://www.fetalmedicine.com/


Liao A, Heath V, Kametas N, Spencer K, Nicolaides KH. First-trimester screening for tri-somy 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 tri-mester 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 deliv-ery. Ultrasound Obstet Gynecol. 2008 Feb;31(2):147-52.

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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 ultra-sound and maternal serum biochemistry in a one-stop clinic: a review of three years ex-perience. 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 syn-drome. Ultrasound Obstet Gynecol. 2007 May;29(5):527-32

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5. RISKS

The risk algorithm for trisomy 21 is built on the idea of contingent screening:

First-line screening is based on maternal age, fetal NT and serum biochemistry. 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 PI• Tricuspid flow• Nasal bone

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• Additional markers: Ductus venosus PI, Tricuspid blood flow, Nasal bone• Major defects

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

The T13 risk is adjusted by (and in the following order):• Age & gestation adjusted risk +/- previous history of T13• NT +/- biochemistry• Additional markers: Ductus venosus PI, Tricuspid blood flow, Nasal 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 limitsTruncation 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 500xT18 3x 500xT13 4x 500x

Biochemistry alone T21, 18 or 13 7x 60xNT and other USS findings

T21, 18 or 13 20x 1000x

NT and biochemistry alone

T21, 18 or 13 20x 1000x

NT, biochemistry and other USS findings

T21, 18 or 13 33x 1000x

The highest risk that can be given is fixed at 1 in 2.

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 disjunction, 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% FPRNT + biochemistry 92%NT + NB, TR, DV, biochemistry 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 andserum 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

Maiz N, Wright D, Ferreira AFA, Syngelaki A, Nicolaides KH. A mixture model of ductus venosus pulsatility index in screening for aneuploidies at 11-13 weeks" gestation. Fetal Diagn Ther. 2012; 31:221-229.

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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.

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

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6. RISKS FOR PREGNANCY COMPLICATIONS

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 anti-hypertensive 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 racial origin, maternal weight and prior or family history of PE, and the following measurements taken at 11-13 weeks:

• maternal blood pressure (MAP)• uterine artery mean pulsatility index (PI)• maternal serum PAPP-A• maternal serum PlGF

Screening by this combined approach could identify about 95% and 45% of patients developing early-PE and late-PE, respectively, at a false positive rate of 10%.

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

Fetal Growth Restriction

Delivery of small for gestational age (SGA) neonates can be predicted at 11-13 weeks’ gestation by a combination of maternal demographic characteristics, including medical and obstetric history, uterine artery pulsatility index (PI), mean arterial pressure (MAP) and maternal serum biochemical markers.

As with preeclampsia, different combinations of markers can be used. Up to 55% of pregnancies which will develop FGR can be identified for a false-positive rate of 2%.

The importance of first trimester screening for these conditions is that their prevalence may be decreased by therapeutic interventions, such as the prophylactic use of low-dose aspirin.

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Risk cutoffs for preeclampsia and fetal growth restriction have been calculated for each combination of markers to achieve a screen-positive rate of 10%. These are shown in the following table, together with the detection rates for early preeclampsia, late preeclampsia, early FGR and late FGR. The risks are PE34 (the risk for PE before 34 weeks) and FGR37 (the risk of FGR before 37 weeks). A pregnancy is considered at risk (in the top 10%) if either PE34 or FGR37 is above the respective cutoff. Risks above the cutoff are printed in bold in the report.

Risk cutoffs Detection ratesFalse positive rate

Screening PE34 FGR37 PE<34 PE≥34 FGR<37 FGR≥37History only 150 100 54.2 40.0 33.5 23.5 12.5PAPPA 150 100 57.0 39.0 42.6 25.1 11.3PlGF 150 100 72.4 33.7 42.9 25.1 10.2PAPPA+PlGF 150 150 76.2 35.4 52.3 31.8 11.5Uterine 150 100 74.3 33.8 41.3 24.2 10.7Uterine+MAP 150 150 90.2 43.6 46.1 42.1 11.9PAPPA+Uterine 150 150 77.6 36.1 53.5 30.3 11.6PAPPA+PlGF+Uterine 200 150 88.8 38.8 59.0 34.2 12.3PAPPA+Uterine+MAP 200 150 93.9 49.8 54.5 45.0 12.6PAPPA+PlGF+Uterine+MAP 200 150 95.3 45.6 55.5 44.3 10.9

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Spontaneous Preterm Delivery

In singleton pregnancies resulting in spontaneous preterm delivery cervical length at 11-13 weeks’ gestation is shorter than women delivering at term. An algorithm combining maternal characteristics and cervical length can identify about 55% of pregnancies resulting in delivery before 34 weeks at a false positive rate of 10%.

The calculation of risk for spontaneous preterm delivery before 34 weeks uses maternal history and characteristics:

• age • height• racial origin• smoking in this pregnancy • method of conception• obstetric history

The relevant values from obstetric history are

• number of spontaneous deliveries between 16-30 weeks• number of spontaneous deliveries between 31-36 weeks• number of all deliveries after 37 weeks

The a priori risk calculated from these values can be used alone, but for effective first trimester screening for preterm delivery it should be combined with the measurement of cervical length. This is not as easy as in the second trimester, so sonographers should be trained to be able to acquire appropriate measurements.

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

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

Akolekar R, Syngelaki A, Poon LCY, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Thera. 2012 Aug 16. Epub ahead of print.

Wright D, Akolekar R, Syngelaki A, Poon LCY, Nicolaides KH. A competing risks model in early screening for preeclampsia. Fetal Diagn Ther. 2012. Pub online 2012 July 27.

Poon LC, Zymeri NA, Zamprakou A, Syngelaki A, Nicolaides KH. Protocol for measurement of mean arterial pressure at 11-13 weeks' gestation. Fetal Diagn Ther. 2012;31(1):42-8. Epub 2012 Jan 13.

Poon LC, Syngelaki A, Akolekar R, Lai J, Nicolaides KH. Combined screening for preeclampsia and small for gestational age at 11–13 weeks. Fetal Diagn Ther. 2012 Sep 13. Epub ahead of print.

Poon LC, Volpe N, Muto B, Syngelaki A, Nicolaides KH. Birthweight with gestation and maternal characteristics in live births and stillbirths. Fetal Diagn Ther. 2012. Pub online 2012 July 26.

Greco E, Gupta R, Syngelaki A, Poon LCY, Nicolaides KH. First trimester screening for spontaneous preterm delivery with maternal characteristics and cervical length. Fetal Diagn Ther. 2012; 31: 154-161.

Beta J, Akolekar R, Ventura W, Syngelaki A, Nicolaides KH. Prediction of spontaneous preterm delivery from maternal factors, obstetric history and placental perfusion and function at 11–13 weeks. Prenat Diagn 2011; 31: 75–83.

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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

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(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 FMF internet based course on the 11-13 weeks scan and submitting the appropriate logbook of images.

Requirements for Certification in the measurement of nuchal translucencyThe 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 boneThe incidence of an absent nasal bone is related to NT, CRL and racial 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 findingsThe 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



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 findingsThe 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



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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Appendix 5

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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Appendix 6

Protocol for measurement of endocervical and isthmic length

In the majority of women undergoing cervical assessment before the development of the lower uterine segment, there is a persistent myometrial thickening between the endocervix and the gestational sac (Figure 1). This thickening is likely to represent the isthmus rather than a contraction. Consequently, in the measurement of cervical length, which for the purpose of clarity we define as endocervical length, we undertake the following steps.

Women are asked to empty their bladder and are placed in the dorsal lithotomy position. The vaginal transducer (2.7–9.3 MHz) is introduced in the anterior fornix of the vagina

and adjusted to obtain a sagittal view of the entire length of the cervical canal, which may be either translucent or echodense. The canal is bordered by the endocervical mucosa, which is usually of decreased but occasionally of increased echogenicity compared to the surrounding tissues.

The probe is withdrawn until the image is blurred and then advanced gently until the image is restored without exerting undue pressure on the cervix.

The settings of the ultrasound machine are altered to obtain the widest viewing angle and the magnification is increased so that most of the screen is occupied by the tissues between the external cervical os at one end of the picture and gestational sac at the other end.

Callipers are used to measure in sequence the linear distance between the two ends of the glandular area around the endocervical.

Figure 1: Ultrasound picture illustrating the measurement of the length of the cervix (A to B) and the isthmus (B to C).

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Appendix 7

Protocol for measurement of mean arterial pressure

The mean arterial pressure at 11-13 weeks is increased in pregnancies that subsequently develop preeclampsia and in those that deliver small-for-gestational-age neonates without preeclampsia, but the levels are normal in trisomic pregnancies.

Blood pressure should be taken by automated devices which are calibrated at regular intervals. The women should be in the seating position, their arms should be supported at the level of their heart and either a small (<22 cm), normal (22-32 cm) or large (33-42 cm) adult cuff should be used depending on the mid-arm circumference. After rest for five minutes blood pressure should be measured in both arms simultaneously and a series of two recordings should be made at 1-minute intervals.

Please record the four measurements of MAP (two from each arm). If your machine does not provide measurements of MAP then record the systolic and diastolic measurements and the software will calculate the MAP.

The software will calculate the average of the four recordings and use this value to calculate a multiple of the median (MoM) corrected for maternal weight, which is then used to estimate the patient specific risk for pregnancy complications.

Poon LC, Zymeri NA, Zamprakou A, Syngelaki A, Nicolaides KH. Protocol for measurement of mean arterial pressure at 11-13 weeks' gestation. Fetal Diagn Ther 2012;31:42-8.

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03 Guide for the First Trimester Screening Module

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