The risk for a baby to be affected by Down syndrome can be calculated based upon maternal age, nuchal translucency measurement and blood tests drawn from the mother at 10 to 13 weeks and again at 15 to 20 weeks into the pregnancy. Ultrasound can be very helpful in refining the risk calculations.
Since the 1970s, physicians performing ultrasound scans have tried to identify ultrasound markers that are not truly abnormalities, but occur more commonly in Down syndrome than in non-Down syndrome pregnancies. Each ultrasound center uses the published literature together with its own experience to identify the markers that they feel are most effective for their population.
A number of groups in this country and abroad have looked at potential sonographic “flags” for Down syndrome visible at the time of the genetic scan. The list of characteristics that have been investigated includes forebrain measurement, nuchal skin fold measurement, echogenic cardiac focus, relatively short femur and short humerus, iliac wing angle, fetal foot length, ear length, examination for clinodactyly and for sandal-strap toe, assessment of the nasal bone, and assessment of various features of the heart. Among these, the markers that have proven to be the most important are evaluation of the nasal bone, linear arrangement of the tricuspid and mitral valves within the heart, thickened nuchal skin fold, slightly short humerus relative to head size, slightly short femur relative to head size, echogenic intracardiac focus, and fetal hydronephrosis.
There are certain ultrasound abnormalities that dramatically change the risk calculation. For example, the finding of a major heart defect may place the pregnancy at a risk of 30 percent or more for chromosomal problems. Mildly enlarged ventricles of the baby’s brain (ventriculomegaly), a small hole in the heart (ventricular septal defect), or a very bright appearance to the baby’s bowel (hyperechogenic bowel) places the pregnancy at a risk of 1 to 10% for Down syndrome, depending upon the remainder of findings on the scan, and individualized genetic counseling would be recommended.
The posterior nuchal skin fold was the first ultrasound marker identified for Down syndrome, and remains a very important one. The posterior nuchal skin fold is the distance between the bone of the back of the head, and the overlying skin. In our review of the literature, and in our own experience, we view a posterior nuchal skin fold of greater than or equal to 5 mm at 15 to 18 weeks, and greater than or equal to 6 mm at 18.1 to 20 weeks as being an increased nuchal skin fold. An increased nuchal skin fold does not mean that the baby has Down syndrome or any other abnormality, but is an important risk adjuster. If mom has already had quad screening, and we have a risk calculation, we multiply the risk number by a factor of 17. For example, if mom had a risk calculation before of 1 per 1,000, this would increase the chance of Down syndrome to 17 per 1,000, or 1.7 percent – a much higher number.
If mom has not already had a risk calculation via the state’s Prenatal Screening Program, we can use either the Down syndrome risk based upon her age, or, if she is still less than 20 weeks into the pregnancy, can draw a quad screen, and wait for the results.
It is important to realize that about 1 in 200 babies will have a thickened nuchal skin fold and will not have Down syndrome. When we see a thickened nuchal skin fold, apart from the Down syndrome issue, we do recommend a very detailed examination of the baby’s heart, called a fetal echocardiogram, at 22 weeks into the pregnancy.
There are two additional high-level risk adjusters for Down syndrome: a nonossified nasal bone and linear arrangement of the tricuspid and mitral valves within the baby’s heart.
Linear arrangement of the mitral and tricuspid valves within the heart. This is sometimes identified, but usually not until 20 or 22 weeks into the pregnancy. A linear valve arrangement flags the pregnancy for evaluation by detailed cardiac sonography (echocardiography) to make certain that a structural heart defect is not present. Among babies who have linear arrangement of the tricuspid and mitral valves, but do not have a heart defect, there appears to be a markedly increased risk for Down syndrome. While the precise figure is still in question, data suggests that it increases the Down syndrome risk by a factor of 30 to 60.
Nonossified nasal bone. If the baby shows a good profile view during the scan, then we can assess to see whether there is a solid and visible ridge of bone within the top of the nose at the 15- to 22-week mark. Depending upon ethnic group, between 0.5 and 10 percent of babies will not show bone formation in the nasal bridge by 22 weeks. An active area of investigation within maternal-fetal medicine is to determine exactly how to incorporate this information into Down syndrome risk calculation. At the present time, we believe that a nonossified nasal bone between 15 and 22 weeks increases the Down syndrome risk by a factor of between 30 and 60.
When we perform ultrasound scans, our computer calculates a ratio between the length of the humerus (upper arm bone) and the average humerus length based upon baby’s head size. A slight variation downward in this ratio has been found to be an important mid-range soft marker for Down syndrome, increasing the risk by a factor of 6. The information is used together with mom’s integrated screen results, just as for a thickened nuchal skin fold. For example, if mom had a 1 in 1,000 risk to start with, the recalculation would be 6 per 1,000. A humerus measurement that is slightly less than expected does not typically mean that the baby has any abnormalities, but we will look at the full body proportions of the baby. A humerus measurement that is far below the expected range, or long bones that have abnormalities in their appearance, such as in-utero fractures, can be an important sign of abnormalities of the skeletal system.
The ratio between measured and expected size of the femur (bone of the upper leg) is also a soft marker for Down syndrome, if it falls below a certain threshold. This calculation is done by our ultrasound computer along with the humerus calculations. Femur length measurement less than threshold increases the risk calculation by a factor of about 2.2.
Echogenic left ventricular foci are the most common Down syndrome risk adjuster that we see on scan. Echogenic foci are bright reflections from the heart muscles. Many parents become concerned that this may represent a heart defect. In fact, a single echogenic focus is seen in 5 percent of all pregnancies, and does not bear any relationship with heart abnormalities of the baby. However, it is a low-level risk adjuster for Down syndrome, increasing the risk assessment by a factor of 2.
The lowest level risk adjuster for Down syndrome is the finding of a small amount of extra fluid within baby’s kidneys. The normal amount of urine that we see within the kidneys between 15 and 22 weeks is less than 4 mm. If we see 4 mm or more, this is considered to be a soft marker for Down syndrome, with a risk adjustment value of 1.5. We see extra fluid in the kidneys in between 1 and 2 percent of all pregnancies. This does bear follow-up later on, because, if extra fluid within the kidneys persists throughout the pregnancy, there can be important recommendations made to protect baby’s health after birth.
Soft Markers after Integrated Screening
An important area of research in Maternal-Fetal Medicine is how the “soft markers” should be used in risk calculation for women who have already undergone nuchal translucency screening. This is an issue that generates controversy and debate whenever Maternal-Fetal Medicine specialists meet. At the present time, our approach is to use the information from the genetic sonogram in addition to that from integrated screening results.
Soft Markers and Risk Assessment
It is important to realize that none of the soft markers for Down syndrome are abnormalities. The way that most of these markers were determined is by reviewing either images or videotapes from ultrasound scans done of both normal babies and babies with Down syndrome. If a certain percentage of normal babies carries one of these markers, but a higher percentage of Down syndrome pregnancies carries a marker, then the marker can be used to statistically adjust the Down syndrome risk calculation.
A good example of this is the following:
If we wanted to screen adults for Down syndrome without ever seeing them, we could look at a marker, such as height versus weight. On average, Down syndrome adults are shorter and heavier than non-Down syndrome adults. So, for example, an adult who is 5 feet 7 inches tall and weighs 180 pounds is statistically more likely to have Down syndrome than an adult of the same height who weighs 130 pounds. So, the 180-pound weight at this height would be a risk adjuster, increasing the chance of Down syndrome. It certainly does not mean that the individual has Down syndrome – my weight and height are 5 feet 7 inches and 180 pounds.
Overall, about 7 percent of pregnancies will show a soft marker increasing the risk calculation for Down syndrome. About 93 percent of pregnancies will show no soft markers, and when no soft markers are seen, the Down syndrome risk calculation is lowered. We multiply the risk calculation by a factor of 0.4, so that if the risk calculation was 1 per 1,000, and no soft markers are seen, then our final risk calculation would be 0.4 per 1,000.
Soft Marker Screening Plus Testing
By combining soft marker screening with amniocentesis, we can increase the Down syndrome detection rate dramatically. For example, if all women with a risk calculation of 1 in 200 or higher choose to have an amniocentesis, we would detect more than 90 percent of babies with Down syndrome.
It is important to recognize that each family will make an individual decision about whether to have an amniocentesis test or not. Neither our center, nor any other prenatal diagnostic center, can diagnose or exclude numeric chromosomal abnormalities, such as Down syndrome, without amniocentesis or CVS testing. Some families want to know for sure, and, therefore, will choose to have an amniocentesis or CVS, without going through any risk calculations. Other families will decide in advance that they would not wish to have an amniocentesis or CVS test regardless of risk calculation. Most families will look at the risk calculation, and compare this with the risks of amniocentesis and CVS testing, and decide whether they wish to proceed.
It has been wonderful to witness the evolution of screening for Down syndrome over the last four decades. In the 1970s, amniocentesis was offered to women over 35, carried a 1 in 200 risk of triggering miscarriage, and in order to detect only about 30 percent of Down syndrome pregnancies, we would have had to perform amniocentesis for 10 percent to 12 percent of all pregnant women. Today, with a combination of integrated screening and soft marker screening, if 5 percent of women opt for amniocentesis, we believe that we can detect about 92 percent of cases of Down syndrome.
Our center is at the forefront of investigating newer technologies that we hope will refine the screening even further. At some point in the future, it may be possible to diagnose Down syndrome by isolating fetal cells from the maternal bloodstream.