Soft markers for clinicians Before you read this section remember the following important points 1. The vast majority of babies with soft markers are normal. 2. Soft markers are frequently seen in healthy babies What is a soft marker? A soft marker is something which may be seen at the time of an ultrasound scan, (usually between 18-22 weeks) which may indicate an increased chance that your baby has Down’s syndrome or another chromosome anomaly but which in itself is probably of little or no significance. Approximately 1:30 babies will have a soft marker detected.

How are soft markers discovered? Soft markers have been discovered in three ways, the first is by chance or a “eureka” moment, the second is by going back to a number of ultrasound images of babies who where born with the problem and seeing if anything unusual can be spotted. Finally we can look at a child born with a condition and then look for the characteristic features seen in children with that disorder to see if we could pick them up on ultrasound.

Who needs an invasive test? This depends on patient wishes, background risks and how much that risk is increased by the particular soft marker.

Nuchal pad measurements The nuchal pad is measured by obtaining a tranverse section through the fetal head which has been angled inferiorly to include a transverse section through the cerebellum. In this plane it should be possible to measure the transverse diameter of the cerebellum, the width of the cisterna magna and the nuchal pad. The calculation from this measurement is different from that of the nuchal translucency measured at 11-14 weeks. The measurement is taken from the outer aspect of the occipital bone to the out edge of the skin. A measurement of 6mm or above is considered abnormal. A thickened nuchal pad can be a marker for all chromosome anomalies. The Meta analysis of Smith-Bindman suggest that this finding increases the Down syndrome risk by a factor of 17. As such even if seen in isolation this is sufficient to warrant offering all women the opportunity of karyotyping. A thickened nuchal pad can also be seen as part of generalised hydrops for which there are many causes and can be seen in association with a cardiac anomaly. This finding therefore necessitates a careful assessment of the fetus. Smith-Bindman r, Hosmer W, Feldstein VA, Deeks JJ, Goldberg JD. Second – trimester Ultrasound to detect fetuses with Down Syndrome. JAMA 2001:285:1044-1054

Choroid Plexus Cyst (CPC) The choroid plexus is found in the lateral ventricle where it is responsible for producing the CSF. During development of this gland its structure is such that fluid is frequently trapped within its substance giving the appearance of a cyst. They are of no functional significance what so ever and there only relevance is that they are a weak marker for Edwards syndrome. To calculate a woman’s risk of delivering a baby with Edwards syndrome first calculate her risk either by looking at a chart for Edwards syndrome or by using her Downs risk and multiplying by 4.5. The finding of a CPC increases that risk by a factor of 8.6 so to calculate her individual risk take her Edwards risk and divide by 8.6. For a 35 year old women her Down’s risk is 1:356. Her Edwards risk is therefore 356 x 4.5 or 1602. The finding of a CPC increases that risk to 1:186 (1602/8.6). Note: NEVER tell a women that her baby has cysts in its brain. Although this is technically true in the sense that they are within the structure of the brain they are not with the substance of the brain. Such comments are very harmful and create lasting memories which are hard to eradicate. The debate has raged in the UK for some time and more recently in the USA as to whether parents should be informed of this finding. Simplistically there are two opposing views: those that believe a woman should be told everything and they should then make up their own mind and those who believe that the anxiety generated is not worth it and therefore withhold the information. Current belief in the region is that the finding of a CPC should warrant a careful search for other anomalies including evidence of overlapping of the fingers. In the absence of these features in women under the age of 35 they should not be reported. If any other marker is seen of if the women are over the age of 35 then they should be reported and the women counselled accordingly. Even then the risks are very small as at 35 one can state that the chance of the baby not having Edwards is 99.5% and even at 41 the chance that the baby does not have Edwards syndrome is 98%. Our reason for this policy is that we have evidence from long term follow up studies that a few women remain anxious about the finding of a CPC well into their child’s life. We have taken the clinical decision therefore that in the interest of the population at large then it is better to withhold that information when we believe the cyst to be isolated. There is no association between CPC and Down’s syndrome.

Echogenic bowel Echogenic bowel is defined as bowel as bright as bone at the time of the anomaly scan. The best way of testing for this is to turn the gain down until the fetal bones start to disappear on scan. If the bowel echogenecity is still visible at this point then the diagnosis is made. It has to be remembered that echogenic bowel is a very subjective diagnosis and can vary from machine to machine depending on the presets of that machine. It will also vary between operators and within the same operator at different times. Echogenic bowel has been linked with a number of potential fetal complications which include, chromosome anomalies, cystic fibrosis, a fetal viral infection, usually CMV, intrauterine growth restriction, and bleeding into the amniotic cavity. The mechanism behind the echogenicity remains unclear but may be due to the presence of blood in the lumen of the bowel, altered peristalsis, bowel wall ischaemia, altered composition of meconium or an as yet undefined cause. Incidence 1:200 -500 at 20 weeks. Risks Risk of chromosome anomaly LR 6.1 ( to calculate take age risk / 6.1) 1-5% risk of CF 1% risk of viral cause 10% risk of birth under tenth centile (? Relevant) Slight increased risk of intrauterine death If found in association with other anomaly / soft marker Chromosome risk becomes higher than risk of loss following invasive testing (1-2% but depends on other anomaly / soft marker and number) CF risk falls Viral cause becomes less likely unless could also be seen in association for example intracranial calcification. Management. - isolated Calculate risk of chromosome anomaly and offer invasive testing if appropriate. Offer testing of both parents for CF deletion screening.(10 days for results) Take maternal blood sample for a TORCH screen, and Parvovirus (10 days for results) Ultrasound biometry, including uterine artery and umbilical cord Doppler. In our experience the fetus who is at significant risk of severe IUGR will already show evidence of this at the time of diagnosis, however we would recommend a growth scan at 28-30 weeks. (If parents opt for karyotyping must indicate this on cytogenetic form so that an appropriate sample can be passed on to the DNA lab for CF mutation analysis.)

CF deletion screening The initial point mutation, delta f508, was identified in the late 1989. Since then over 600 other mistakes in the CF gene have been identified. It is obviously not possible to test for all mutations and current analysis checks for the commonest 36. The risk of a white Yorkshire resident carrying a mutation in either CF gene is 1:22. As screening does not identify all mutations a negative result decreases the risk from 1:22 to 1:100. If both partners are negative then the residual chance of the child having CF is 1/100 x 1/100 x ¼ of 1:40000. The problem arises if one partner screens positive. Technically using the above logic the risk should be 1/100 x 1 x ¼ or 1:400. This does not however take into account the a priori risk generated by the echogenic bowel which would increase this risk.

Short femur Defined as a measurement under the 3rd centile Short femurs are a very weak marker for Down syndrome LR 2.7. This risk should not be discussed with the parents or reported if the maternal age is under 35 or the women has screened low risk on biochemical testing. A short femur could be indicative of genetically small baby, IUGR, a focal problem with one or both femurs or as part of a skeletal dysplasia. Management Family history to include the size of both parents and possibly grandparents. Careful fetal assessment with in addition to a full anomaly scan an assessment of the other long bones, the spine, skull and fetal chest. The assessment of the bones should include the echogenicity, whether they are straight, evidence of fractures, mineralisation of the skeleton, and the size of the chest. If the cause of the short femur appears to be familial then there is probably little need for a repeat ultrasound. If however the femur is below the 3rd centile or there is no obvious cause I would suggest a repeat assessment in 2-4 weeks time. The purpose of the repeat scan is to assess long bone growth over the time period. If it has been appropriate than no need for a repeat assessment if growth falling father behind consider that this may be a skeletal dysplasia and may need fetal medicine review.

Renal dilatation Mild renal dilation usually defined as a renal pelvic dilatation of between 5/6 – 10 mm at the time of the mid pregnancy scan carries a small increased risk of Down’s syndrome. However this risk is not felt to be of sufficient impact to alter a woman’s age related risk (LR 1.9). The significance of this feature is far more likely to relate to the possible association with renal pathology and even then these risks are small. The two common conditions seen with renal dilatation are reflux and a PUJ (pelviureteric junction obstruction) The significance of these is that in the former, an infection in postnatal life, within the bladder will be refluxed back to the kidney. As a baby is unable to communicate loin pain these infections can pass undetected and can lead to long term scaring of the kidney and renal failure. Unfortunately the postnatal test for this is a micturating cystourthrogram which is invasive and therefore not without risk. A PUJ obstruction if severe will lead to back pressure on the fetal kidney and can cause significant damage. This is unlikely to occur when the renal pelvic dilatation is under 15mm and highly unlikely with a diameter of 10mm or less. Current management for isolated mild renal dilation is to arrange a third trimester ultrasound to assess the diameter. This is done in order to be able to time the urgency of postnatal ultrasound - see renal pathology section for more details. For an isolated finding in a screened women there is no reason to change her Down’s risk

Echogenic foci in the fetal heart. Echogenic foci in the fetal heart are thought to arise as a result of calcification within the papillary muscle. They appear to be of no short or long term clinical significance other that a very week association with Down’s syndrome. The likelihood ratio (LR) has been calculated at 2.8. In isolation they do not warrant a detailed cardiac scan or any specific follow up.

Advice from the national screening committee re soft markers The NSC has agreed that the following soft markers found in isolation in a women who has already undergone biochemical screening should be discounted: • Head shape • Choroids plexus cyst • Sandal gap • Two-vessel cord • Cisterna magna • Clenched hand • Clinodactyly • Echogenic foci in heart • Short humerus This of course does not answer the question of what should be done if the woman has not undergone biochemical screening or if more than one marker is seen. In that situation each case should be taken on its merits. It is very hard to be didactic as the risks would depend on which markers had been seen and the a priori risk based on the maternal age. For example a thickened nuchal pad and echogenic bowel in a 20 year old might be of greater significance than a slightly short femur and 5 mm renal pelvic dilatation in a 35 year old.