PRENATAL TESTING

It is known that half of early pregnancy losses are due to major chromosomal abnormalities in the baby. Miscarriage analysis can be particularly important for women suffering from recurrent pregnancy loss so as to understand why they miscarried and if they are at risk for subsequent miscarriages.

CONVENTIONAL APPROACH: Routine karyotyping

Challenge

Karyotyping requires living fetal cells to be grown in culture, and up to 50% of the time karyotyping will not provide a result as the cells sometimes fail to grow in culture. This can be frustrating because most labs will attempt to culture the cells for up to three or four weeks before determining that the miscarriage test is a failure. Furthermore, when cells are grown in culture, it is also possible that new chromosomal abnormalities develop that were not originally present (culture artifact). This is problematic because recurrence risk counseling is based on the type of chromosomal abnormality identified.

Solution – Chromosomal Microarray Testing

A better technology for miscarriage testing, that is based on the sampling of patient’s whole genome against a reference normal genome using molecular biology techniques is available. The technique is able to detect very small changes in the genome of the patient which can cause recurrent miscarriages or other abnormalities in the fetus. These smaller changes cannot be detected by karyotype. Larger changes such as chromosome 13, 18 or 21 and the loss of heterozygosity which increases the risk of recessive disorders are also identified.

CMA is particularly valuable in detecting copy number variations or loss of heterozygosity regions in cases where karyotype is normal but abnormal ultrasound findings are present. Abnormalities may be detected even in fetuses with normal karyotypes as well as normal ultrasound scans.

“It does not always mean that a child will necessarily develop disorders, because many are due to multiple influences. But it will help parents because they can be on the lookout for a particular disorder and have a treatment plan in place. I believe it is important to give parents as much information as they need about their child.”*

*Dr. Ronald Wapner, director of Reproductive Genetics at NewYork-Presbyterian Hospital/Columbia University Medical Center and vice chairman for research and professor of obstetrics and gynecology at Columbia University College of Physicians and Surgeons.

Prenatal Testing: Tests for diseases or conditions in a fetus or embryo to enable timely medical or surgical treatment of a condition before or after birth, to give the parents the chance to abort a fetus with the diagnosed condition, and to give parents the chance to “prepare” psychologically, socially, financially, and medically for a baby with a health problem or disability, or for the likelihood of a stillbirth.

A test considered medically necessary for the evaluation of a fetus for ANY of the following:

  • Abnormal fetal anatomic findings which are characteristic of a genetic abnormality; or
  • Fetal demise with congenital anomalies; or
  • In patients with a structurally normal fetus undergoing invasive prenatal diagnostic testing; or
  • The individual is considered at high risk for fetal chromosomal aberrations due to ANY of the following:
    1. The expectant mother is 35 years or older at the time of delivery; or
    2. The expectant mother has a history of a prior pregnancy with a trisomy; or other chromosomal defects
    3. The expectant mother has a positive first or second-trimester standard biomarker screening test.

The American college of obstetricians and gynecologists(ACOG)/Society for Maternal-Fetal Medicine(SMFM)

  • For fetuses with abnormal ultrasound findings having invasive prenatal diagnosis.
  • Either CMA or standard karyotyping for fetuses with normal ultrasound findings having invasive prenatal diagnosis.
  • For women of any age undergoing invasive prenatal diagnosis, because the anomalies detected do not correlate with maternal age.
  • CMA as the method of choice to analyze genetic material in cases of fetal demise or stillbirth.

“With karyotyping, we can see only when pieces of the genome of about 5 million base pairs are missing from a chromosome. With CMA, we can see missing pieces of fewer than 100,000 base pairs.”

“In 6 percent of the cases where there’s a structural abnormality of the fetus but karyotyping is normal, CMA will provide additional significant information. And in about 1.7 percent of cases where the procedure was done because of the mother’s age or similar concerns and the chromosomes were normal, CMA reveals additional information of concern.”

AUTOMATED

CMA has less human intervention and evaluates fetal DNA directly unlike karyotyping which is a subjective test that depends solely on the expertise of technician & cytogeneticists and is subject to culture artifact in 50% of cases.

EVALUATION OF FETAL DEMISE OR STILL BIRTH

CMA analysis does not require cultured cells. Viability does not come into play at all –DNA can be extracted from tissue that is not living (from product of conception (POC) samples & still births).

MORE SENSITIVE

CMA can identify submicroscopic abnormalities such as translocations, micro deletion or micro duplications disorders more likely to be associated with later pregnancy losses that are missed by karyotyping.

MORE INFORMATIVE

CMA detects copy number variations or loss of heterozygosity regions in cases of normal karyotypes and abnormal / normal ultrasound findings.

FASTER TURN AROUND TIME

CMA eliminates the need to culture cells, therefore turn around the analysis in 10 days, as opposed to 3 weeks by karyotyping.

HIGHER RESOLUTION

CMA yields greater detection rate and precise location of Copy number variations.

Submit only 1 of the following specimen types

Type: Amniotic Fluid

Specimen Requirements:

Collect 20-30 ml of amniotic fluid (discard the first 1-2 ml). Place in sterile conical centrifuge tubes.

For cultures: 1 T75 or 2 T25 at 70% confluency.

Specimen Collection and Shipping: Ship sample at room temperature for receipt at iLife within 24 hours of collection. Do not refrigerate or freeze.

Type: Chorionic Villi

Specimen Requirements:

Collect 15-30 mg of chorionic villi using sterile technique. Place in sterile tube(s) with iLife transport media or other sterile culture media.

For cultures: 1 T75 or 2 T25 at 70% confluency.

Specimen Collection and Shipping: Ship sample at room temperature for receipt at iLife within 24 hours of collection. Do not refrigerate or freeze.

Type: Cord Blood

Specimen Requirements:

In sodium heparin (green top) AND EDTA (purple top) tube: 1-3 ml of fetal blood (PUBS)

Specimen Collection and Shipping: Ship sample at room temperature for receipt at iLife within 24 hours of collection. Do not refrigerate or freeze.

The Use of Chromosomal Microarray Analysis in Prenatal Diagnosis- The American Society of Obstetricians and Gynecologists/The Society for Maternal-Fetal Medicine Committee Opinion. Number 581, December 2013.

http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Genetics/The-Use-of-Chromosomal-Microarray-Analysis-in-Prenatal-Diagnosis

RJ Wapner et. al. Chromosomal Microarray versus Karyotyping for Prenatal Diagnosis. New Engl J Med 2012 367 (23) 2175-2184.
http://www.nejm.org/doi/full/10.1056/NEJMoa1203382

MS Savage et. al. Evolving applications of microarray analysis in prenatal diagnosis. Curr Opin Obstet Gyn 2011, 23:103–108
http://www.med.stanford.edu/content/dam/sm/cirge/documents/activities/journalclubs/Current%20Opinion%20in%20Obstetrics%20and%20Gynecology%202011%20Savage.pdf

LG Shaffer et. al. Experience with microarray-based comparative genomic hybridization for prenatal diagnosis in over 5000 pregnancies. Prenat Diagn 2012 Oct;32(10):976-85.
http://onlinelibrary.wiley.com/doi/10.1002/pd.3945/full

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