Another year, another change in prenatal testing recommendations by ACOG

Last year, the American Congress of Obstetricians & Gynecologists (ACOG) issued its position statement on non-invasive prenatal screening, recommending it be offered to high-risk expectant mothers. This year, ACOG, along with the Society for Maternal-Fetal  Medicine, recommends a new form of diagnostic testing for expectant mothers.

ACOG Committee Opinion No. 581 is titled The Use of Chromosomal Microarray Analysis in Prenatal Diagnosis. Let’s first deal with what microarray is, and then how ACOG recommends that it be used.

I have criticized the analogy that our genetic code can be likened to a set of encyclopedias–because that suggests there is a stock set and any variation is a defective set of World Books. But, for purposes of explaining microarray, the analogy may be useful.

The traditional genetic chromosomal diagnostic test was a karyotype. Most of us who are parents of children with Down syndrome received a copy of our children’s karyotype, which showed the squiggly paired lines for 22 of the chromosomes, and then, with the pair at Chromosome 21 there was a third squiggly line. Well, think of karyotyping as images of the individual volumes in the set of encyclopedias, e.g. two Vol. A’s, two Vol. B’s, … three Vol. U’s (the 21st letter).

Microarray, on the other hand, is an image of the individual pages in the volumes. So karyotyping diagnoses the individual chromosomes/individual volumes, while microarray diagnoses the individual genes/individual pages on the chromosomes/in the encyclopedia volumes.

ACOG highlights these differences between microarray versus karyotyping in its committee opinion:

1. “The primary advantage of chromosomal microarray analysis over the conventional karyotype is the higher resolution, which yields more genetic information.”
2. Microarray testing is standardized, through computer analysis, whereas karyotyping involves microscopic staining of chromosomes, and therefore microarray may be less prone to human error.
3. Microarray, however, cannot detect balanced inversions, balanced translocations, or all cases of tissue mosaicism, unlike karyotyping.

There is another limitation to microarray that ACOG highlights, and should be appreciated:

A limitation of chromosomal microarray analysis is the potential to identify copy number variants of unknown clinical significance. … That is, such results indicate a susceptibility to a particular outcome, such as autism, but not a certainty that this will occur. In some cases, evaluation of parental samples can help clarify whether or not this is an inherited finding or a new finding in the offspring; however, the clinical outcome may remain unclear.

Because microarray is looking at the individual genes, not just the whole chromosome, it can detect thousands of possible variations, but what those variations mean, and whether they will mean anything, is sometimes unknown. So, those seeking information prenatally will be provided more information, but what that information means may be unknown.

Nevertheless, ACOG makes the following recommendations:

• In patients with a fetus with one or more major structural abnormalities identified on ultrasound and who are undergoing invasive prenatal diagnosis, chromosomal microarray analysis is recommended. This test replaces the need for fetal karyotype.
• For patients with a structurally normal fetus undergoing invasive prenatal diagnostic testing, either fetal karyotyping or chromosomal microarray can be performed.
• [Importantly] comprehensive patient pretest and posttest genetic counseling from qualified personal such as a genetic counselor or geneticist regarding the benefits, limitations, and results of chromosomal microarray analysis is essential. Chromosomal microarray analysis should not be ordered without informed consent, which should be documented in the medical record.

That last bullet point is supposed to address the ethical concerns about reporting more information of unknown relevance to anxious parents. Whether that is sufficient for justifying offering microarray to all women undergoing invasive testing will be the subject of the next post on these new recommendations. (That critique will be based on the 13th reference listed in the recommendations).

But, in the end, for the second year in a row, ACOG has made a major recommendation changing how prenatal testing is to be administered. Whether we’re ready for it or not.