Most of you know about amniocentesis and chorionic villus sampling (CVS…not the drugstore!). A quick review: Since the 1960s women over 35 were told that they had an increased risk of having a child with the extra chromosomal that caused Down’s syndrome and that once pregnant this could be detected with amniocentesis. (A procedure in which amniotic fluid is withdrawn with a long needle inserted through the abdominal wall into the uterus at around 16 week’s gestation. Cells from the fluid are then cultured for 10 to 14 days and stained so that the chromosomes can be counted.) CVS procedure was developed in the 80s. (Cells obtained from the edge of the placenta are identical to those of the fetus. They can be obtained with an instrument inserted through the cervix under ultrasound guidance as early as 10 week’s gestation.They are then immediately stained and their chromosomes are counted and analyzed and in most cases allow for an early diagnosis.)
Noninvasive prenatal testing was developed in the 1970s when the first ultrasounds produced two dimensional images of the fetus in the uterus. Initially ultrasound was used for measurements to determine gestational age and later to view anatomy. And as ultrasound developed, a maternal blood test of a protein called alpha-fetoprotein was found to be associated with open neural- tube defects (spina bifida) and other fetal abnormalities if high and if low, Down’s syndrome. As these noninvasive ultrasounds and blood tests became more less expensive, “blessed” and backed by the major medical organizations, they were offered to pregnant women of all ages. Meanwhile, back at the ultrasound, engineers and radiologists improved the imaging devices, went to real time and three dimensions. This allowed physicians and their patients to view fetal cardiac, neural and skeletal development. The perinatologists also found that ultrasound in early pregnancy allowed them to measure the thickness of the tissue at the nape of the neck (nuchal fold) which could then help foretell fetal chromosomal abnormalities. This was added to the armamentarium of noninvasive prenatal testing.
This long introduction to prenatal diagnosis is my way of getting to an article in the New England Journal of Medicine that appeared in the February 27 issue. It basically is a “We have come a long way baby” introduction to a new noninvasive test using maternal blood to access fetal chromosomes. The actual fetal DNA is analyzed from small fragments of cell-freeDNA (cfDNA) that are shed from the placenta into the maternal circulation. The amount of fetal cfDNA in maternal blood increases rapidly at the onset of embryo development so that it represents about 10% of free DNA in maternal blood during the first and second trimesters. Currently a method called massive parallel sequencing (or if you care to know, next generation sequencing) which reads millions of sequences along the length of each chromosome can be used to determine abnormal fetal chromosome number (termed aneuploidy) in maternal blood.
The current study was carried out at 21 centers in the United States. Blood was collected from women with single pregnancies who were undergoing the standard screening of blood biochemical methods (which included a few more than outlined above) with or without ultrasound measurement of the nuchal fold in the fetus. The researchers compared rates of detection of certain extra chromosomes (that is three instead of two) in trisomy 21 or Down syndrome and trisomy 18 between the fetal cfDNA test and traditional tests. They then examined birth outcomes or chromosomal counts on terminated pregnancies. The series included 1914 women. Fetal cfDNA testing detected all cases of aneuploidy and the false positive rate was significantly lower than detection with standard screening.
A separate editorial in the journal predicts that a negative result in this type of maternal blood screening will help prevent the need for invasive testing. They also state that a positive test is not enough for a final prediction that the pregnancy is abnormal. Women who have a positive fetal cfDNA test will need amniocentesis or CVS to ascertain if the fetus has a triple chromosome 18 or 21. But once this test becomes less expensive, is studied in a larger group of “low risk” women and goes mainstream, the majority of pregnant women may be assured with just this blood test that, if negative, they will not have to undergo further invasive testing.
I know this was a long (and for many uninteresting) analysis of advances in prenatal testing. But for those obstetricians who spent most of their careers helping women ensure the chromosomal health of their pregnancies, and for their future patients, this is an exciting advance.