There were several significant findings: One is that almost one-third of patients have a copy variation now known to be benign. Another is that 2.5% of women who had ultrasound-identified anomalies and normal karyotypes had microdeletion/duplications on the microarray that were clearly associated with a known clinical problem. Moreover, another 3.2% had gains and losses of potential clinical significance. As such, close to 6% of women with ultrasound-identified anomalies and a normal karyotype had clinically relevant copy number variants that only the microarray could find.
When microarray analysis was performed in women whose only indication for prenatal diagnosis was advanced age or an abnormal result on Down syndrome screening, as opposed to an ultrasound-detected anomaly, 0.5%, or 1 in 200, were found to have a pathogenic abnormality that otherwise would have been missed. This is significant: Previously, with karyotyping, we quoted patients a minimum of 1/500 risk of finding a clinically relevant chromosomal anomaly even if the combined report suggested much lower risks of Down syndrome. Now, with microarray, that risk is 1/200. Other studies already published or about to be published show this same level of risk determined by microarray.
With any new technological advance, we get our numerators of the problem before our denominators. The first cases published are those in which clinical or laboratory findings are associated with an abnormality. Only then do researchers go back and look at cases with those findings to test these associations – and only then are the markers sometimes found not to be associated. It will take a number of years to acquire a sizable database on microarray-detected copy number variants. In the end, microarray may help us to explain many of the approximately 1% of serious problems that we have been unable to diagnose until now.
Current decision-making
Ultimately, the future lies with routine, complete genomic sequencing that provides a detailed view of the fetal genome. This is likely to be about 7-10 years away, and the main question on the table is whether it will be performed invasively or with a maternal blood sample.
Today, when a 35-year-old woman comes into my office early in her pregnancy, I will tell her that the risk of having a baby with a chromosomal abnormality is 1 in 190. If she wants to know more, I will explain that the second-trimester quad screen will detect 60% of Down syndrome cases, that the first-trimester combined screen can identify 85% or more, and that the free fetal DNA test will get closer to 99%.
Despite the significant advances in screening, all of these options are still the fundamental equivalent of a Gallup poll. If the patient wants a definitive answer, she will need either an amniocentesis or a CVS, which, in experienced hands, have been shown through an increasing number of studies to be of equal risk. Because there is no such thing as "no" risk when it comes to prenatal diagnostic testing, the question that each patient must answer is, "Where do you want to put that risk – in the test or gambling on the outcome?"
We also have a great cultural divide in the United States. Some people want to know everything, others want to know nothing. Our affluent patients are getting older. Our poorer patients are getting younger. Some people will pay whatever it takes to get the answers they want, while others can or will not pay a dime beyond what their insurance will cover.
There is no one algorithm that can handle these two extremes of patients. Right now, many programs around the country have seen a diminishing number of patients having diagnostic testing – a phenomenon I believe is the result of a false sense of confidence, of people being lulled by the faulty argument that screening protocols can find Down syndrome, so what else is there to know?
Ultimately, a model for younger women would start with "contingent screening," in which patients could start with first-trimester combined screening and move straight to CVS if found to be at "high risk," and end testing if found to be at "low risk." Women who fall in the middle could undergo either free fetal DNA analysis or CVS, and we are developing methods to improve the mathematical processing of data to improve the sensitivity and specificity of all screening programs.
In my program, CVS and microarray are now offered to all patients regardless of age, as the risk that a microarray will find a significant abnormality is at least 1/200, which is the risk we have been quoting to 35-year-old patients for nearly 50 years.