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Prenatal Diagnosis via Amniocentesis and Chorionic Villus Sampling (CVS)

Many inherited conditions can be diagnosed prenatally, via CVS or amniocentesis to obtain fetal tissues to analyze. . These procedures have identified chromosomal abnormalities, such as Down syndrome, and neural tube defects, such as spina bifida. Recently, however, explosive growth in DNA testing technology has made it possible to detect hundreds of additional genetic disorders, including Tay-Sachs, cystic fibrosis, Duchenne muscular dystrophy, and sickle-cell anemia, to name just a few.

We employ molecular technologies that allow us to obtain results for certain conditions such as Down Syndrome, Trisomies 13 and 18, and the sex chromosomes one day after the procedure.

Amniocentesis

Amniocentesis was the first method developed for prenatal diagnosis. It is usually performed between 15 and 20 weeks from the beginning of the last menstrual period. Under the guidance of ultrasound, a very fine needle is inserted through the woman's abdominal wall and into the uterus. Approximately one ounce of fluid is withdrawn and sent to the laboratory for analysis. In experienced hands, genetic amniocentesis is a very safe test. A limitation of amniocentesis is that reassurance or diagnosis of problems does not occur until the second trimester.

Chorionic Villus Sampling (CVS)

Chorionic villus sampling, or CVS, is the first-trimester procedure for prenatal diagnosis of fetal chromosomal and genetic disorders, usually performed 11 to 13 weeks from the beginning of the last menstrual period. The procedure can be done one of two ways. In singleton pregnancies, most of the time we place the patient in stirrups, and a speculum is inserted just as for a Pap smear. A small plastic catheter (similar to a straw) is passed painlessly through the cervix and maneuvered into the placental tissue under ultrasound guidance. A syringe is then attached to the end of the catheter, and a very small amount of tissue is aspirated. In some cases (about 30% of the time for singletons), depending upon the position of the placenta, a needle may be inserted transabdominally and maneuvered into the placenta (not the fluid). In either case, several milligrams of tissue are sent to the lab. Tests can then be performed for chromosomal (e.g. Down syndrome) molecular diagnosis (such as cystic fibrosis, or FISH for a quick read of chromosomes such as Down syndrome), or enzymatic analysis (for some biochemical disorders).

We commonly perform CVS for diagnosis of singleton pregnancies

1. at elevated risk for birth defects; for diagnosis

2. in multiple pregnancies prior to reduction, to help ensure the health of fetuses remaining after the procedure; and

3. for patients who have undergone preimplantation genetic diagnosis (PGD) with in vitro fertilization because they need post-implantation confirmation of the PGD results.

Safety of procedures

For many years, it was a common misconception that amniocentesis was a safer procedure than CVS. Several recent studies have now confirmed (what those of us who have been doing CVS for decades have known) - that CVS is just as safe or safer than amniocentesis. Some operators have quoted amniocenteses risks at 1/1500 or 1/100 depending upon whether they were for or against. Both such extremes are not realistic. On the basis of having done more than 60,000 procedures, in very experienced hands we quote risks of both procedures at about 1/500, although it is likely to actually be less than that. CVS is particularly useful in multiple pregnancies because if a reduction is being considered it is much safer to be done at 12 weeks rather than waiting until about 20 weeks.

Fetal Tissue Sampling

Tests utilizing the DNA in fetal tissues have made possible via CVS the diagnosis of disorders such as Duchenne muscular dystrophy. Sometimes, however, DNA tests cannot give a definitive answer, and the only way to get the answer is by obtaining a piece of fetal muscle, or liver. Over the past 25 years, we have performed more fetal muscle biopsies than anyone else, worldwide.

Similarly, some skin abnormalities and certain chromosomal abnormalities can only be diagnosed by obtaining a piece of fetal skin. Fetal skin biopsy is the optimal way to evaluate ambiguity that occasionally arises in the interpretation of amniocentesis data. These biopsies are performed without a hospital stay, and under ultrasound guidance.

Laboratory Testing

There has been a virtual explosion in the sophistication of laboratory testing available both for screening tests as described above and for direct evaluation of fetal health from CVS, amniocentesis, fetal skin, and fetal tissues.

The traditional test is the karyotype in which cells from tissue specimens are cultured and then organized into groups based upon their size and the centromere which connects a "long" and a "short" arm. There are normally 46 of these – actually 23 pairs. Each of us normally inherits one of each of our parent's chromosomes which pairs up with one from the other parent. When we make our sperm or eggs, one of each of our pairs goes into the sperm or egg. The first 22 pairs are independent of our gender. The last pair, the sex chromosomes, determines gender. Women have two X chromosomes; men have one X and one Y.

The traditional test for the past 4 decades has been the karyotype in which cells from a tissue sample are grown so structures inside the cells, called chromosomes, can be isolated. Chromosomes contain our genes, which are the instructions necessary for proper growth and development. The usual number of chromosomes for humans is 46, or 23 pairs. Normally, each person inherits half of their chromosomes from their mother and half from their father. The first 22 pairs of chromosomes are numbered (1 to 22) and the last pair is given a letter (X or Y). Women usually get an X from mom and from dad – XX. Men get an X from mom and a Y from dad – XY. Each chromosome from mom matches up with one from dad so in the photo below, one of the number 1s is from the mother and the other is from the father. One of the number 2s is from the mother and the other number 2 is from the father, and so on. The numbered chromosomes are the same for men and women. The lettered chromosomes determine sex. If there is no Y, the person is typically female. If there is a Y, the person is typically male.

There are 23 pairs of chromosomes. The first 22 are numbered and one of each pair comes from each parent. The last pair are the sex chromosomes. Women have 2 "X" chromosomes, and men have one "X" and one "Y."

Unfortunately, mistakes sometimes happen. The most common scenario is that in the process of creating eggs for fertilization, the splitting of one of the mother's pair doesn't occur, leading to an egg with two copies instead of one. Then with fertilization, the embryo/fetus has three instead of two.

Below are two karyotypes. The first is of a male with Trisomy 21, more commonly known as Down syndrome. The second karyotype below is a female with Trisomy 18 – a condition with a very high mortality rate and severe disabilities in surviving infants.



Trisomy 21



Trisomy 18



Because our patients are "average New Yorkers" who want their answers yesterday, in addition to the karyotype we also run molecular testing with a technique called fluorescent in situ hybridization (FISH) that gives rapid answers for chromosome 21 (Down syndrome), trisomies 13 and 18, and the sex chromosomes looking for abnormalities but which gives gender as a byproduct. The two figures below show a normal male. The first picture has two copies of Chromosomes 18, one "X" and one "Y." The second shows two copies of chromosomes 13 and 21.

Microarrays

The laboratory technique of array CGH (aCGH), often called microarray, offers more precise identification of additions or deletions of material. aCGH can identify changes far too small to be seen on karyotype. The smallest piece of a chromosome that can generally be seen on karyotype has about 5 million base pairs. The aCGH can get to a resolution of near 200 thousand. Thus, it can be thought of as a 30 fold magnification over the karyotype. For the pediatricians, microarray has already replaced the karyotype. We anticipate that in the next few years microarrays will replace prenatal karyotypes. Below are array depictions of a normal female – two X chromosomes and no Y chromosomes. The second shows three copies of chromosome 21.

For several years in the 2000’s, the general consensus was to restrict aCGH use to those cases in which there was an ultrasound abnormality and a NORMAL karyotype. The 2012 NICHD study showed nearly 6% of such cases have an abnormality of significance on the microarray. The same study demonstrated that for patients with a normal ultrasound having CVS or amniocentesis because of advanced maternal age or because of increased risk on screening tests, the additional detection of significant gain or loss of material is about 1/100 (1.0%) when there is a normal karyotype. The risk is not a function of maternal age. Since this risk number is, in fact, higher than the risk quoted to a 35 year old for traditional aneuploidy (1/200, 0.5), we decided a few years ago that it was time to begin offering aCGH to ALL PATIENTS REGARDLESS OF THEIR ACTUAL AGE. Our own data have shown about a 1% incidence of findings of significance in patients who had no other reason to be considered at high risk.

With every emerging technology there is a period in which certain findings on tests cannot be determined to be abnormal or not. We have seen this, for example, for multiple ultrasound abnormalities such as the choroid plexus cyst and the echogenic focus. During this time, we have "numerators" before we have the "denominators." We now know that about one third of all patients have an addition or deletion of material which we know or strongly believe is benign. However, the chance of having a variation of uncertain significance – meaning we don’t know if it is of clinical significance or not is also about 0.5%. This number will continue to fall with increasing experience. For now patients have to decide whether the increased pick up is worth the potential for increased anxiety without an answer in small percentages of patients. The extent of insurance coverage for microarrays is still questionable for many companies but has improved considerably over the past few years.

The above aCGH shows an unbalanced translocation between chromosomes 13 and 18 that would be expected to have serious consequences for the fetus.

We are now making it our common practice to offer these arrays in most situations. The situation is problematic in patients with multiple pregnancies having reductions as the risk of losing the pregnancy during the several weeks it takes to get the aCGH answer is likely higher than the chance of obtaining an abnormal result.

Fetal Tissue Sampling

Tests utilizing the DNA in fetal tissues have made possible via CVS the diagnosis of disorders such as Duchenne muscular dystrophy. Sometimes, however, DNA tests cannot give a definitive answer, and the only way to get the answer is by obtaining a piece of fetal muscle, or liver. Over the past 20+ years, we have performed more fetal muscle biopsies than anyone else, worldwide.

Similarly, some skin abnormalities and certain chromosomal abnormalities can only be diagnosed by obtaining a piece of fetal skin. Fetal skin biopsy is the optimal way to evaluate ambiguity that occasionally arises in the interpretation of amniocentesis data. These biopsies are performed without a hospital stay, and under ultrasound guidance.

Fetal Therapy

The diagnosis of a serious disorder in a fetus is a devastating event for all involved. In many cases, there may be little that medicine can offer, aside from help in preparing for the birth of child with special needs, or the option to terminate the pregnancy. In some situations, however, there is another alternative: treating the disorder before birth.

We can also provide you with world-class expertise in this area. Dr. Evans:

  • developed the first method for preventing a congenital defect before birth (congenital adrenal hyperplasia);
  • performed the first successful stem cell transplant to cure a baby with SCIDS (the "bubble babies");
  • was a member of the team that did the first successful open fetal surgery (for congenital diaphragmatic hernia); and
  • is one of the most experienced at performing fetal shunt procedures, such as for obstructed fetal bladders. We work with colleagues all over the country to provide cutting-edge therapies in pregnancies with correctable problems.

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  • Quick Contact Info

    Dr. Mark I. Evans (MD PLLC)

    Phone: 212.288.1422
    Fax: 212.879.2606
    Email: Evans@CompreGen.com 131 E 65TH ST
    NEW YORK NY 10065