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Chromosomes are structures in each cell of the body that carry genetic information, or genes, in the form of DNA. Healthy humans normally have 46 chromosomes arranged in pairs: 22 pairs of ‘autosomes’ and one pair of ‘sex chromosomes’ (XX in females or XY in males) for a total of 24 unique chromosomes (1-22, X, Y).

A child receives one of each pair of chromosomes from the mother in the egg and one of each pair from the father in the sperm. Of 46 chromosomes, half come from the mother and half from the father.

Occasionally, an egg or sperm will form with an abnormal number of chromosomes, a condition called aneuploidy. Having an extra chromosome is called ‘trisomy’; a missing chromosome is called ‘monosomy.’

The vast majority of embryos with aneuploidy do not implant in the uterus or are lost in early miscarriage. In fact, over half of all early miscarriages are due to aneuploidy. In some cases, a baby can be born with an abnormal number of chromosomes, a situation usually associated with mental retardation and birth defects, depending on which chromosome is extra or missing. A common type of aneuploidy is Down syndrome, caused by three copies of chromosome number 21 (Trisomy 21). Other common aneuploidies include Trisomy 18, Trisomy 13, Klinefelter Syndrome (XXY), Turner Syndrome (XO), Triple X Syndrome (XXX), and Jacob Syndrome (XYY).

Aneuploidy can happen in any pregnancy, simply by a chance error in the formation of the sperm or egg, or early during embryo development.

Although anyone can have an embryo with aneuploidy, the chance increases with the age of the mother. Additionally, since the majority of fetuses with aneuploidy miscarry, the chance of aneuploidy is higher if testing an embryo, and decreases when testing a fetus (during the pregnancy), or a newborn baby.

About 1 in every 500 live born babies has some type of chromosome abnormality. The rate of aneuploidy in embryos is much higher, reaching 80% in women over 40 years of age. Most of these chromosomally abnormal embryos will either not attach to the uterus or will be miscarried early in pregnancy. This is likely the reason that women, as they age, have more difficulty conceiving and continuing a pregnancy. The risk of aneuploidy in an embryo or baby is illustrated in the chart to the right.

The cells that will eventually become eggs each have 46 chromosomes. These ‘pre-eggs’ are stored in the female ovaries from birth, and women do not make more during their lifetime. After ovulation each month, one of the pre-eggs divides in half, giving one chromosome from each chromosome pair to the mature egg, for a total of 23 chromosomes. As women get older, their pre-eggs get older, too, and the process of chromosome division does not work as well. Thus, as a woman ages, the mature eggs released at ovulation have a higher chance of dividing abnormally and containing extra or missing chromosomes instead of the normal number of 23. The process of abnormal division is called chromosome non-disjunction.

Preimplantation Genetic Diagnosis (PGD) for aneuploidy is a specific type of PGD used with IVF to identify embryos with an abnormal number of chromosomes. One blastomere of each embryo or several cells from a day 5 embryo are evaluated for aneuploidy.

This testing allows IVF physicians to transfer to the mother’s uterus those embryos with no detectable chromosome abnormalities. This may increase the chance that a couple will become pregnant during a particular cycle. It may also decrease the chance for miscarriage during the pregnancy and reduce the chance of having a baby with a chromosome abnormality such as Down syndrome.

Aneuploidy can occur in any embryo from anyone, just by chance, although some people are at a higher risk. This testing technology is new, so clinical data is still pending, but studies have demonstrated that PGD may be particularly beneficial for:

• Women aged 35 and older
• Couples who have had a previous pregnancy with a confirmed chromosome abnormality
• Couples who have had multiple early miscarriages

Studies of couples who have had more than one miscarriage have shown a higher number of embryos with chromosome abnormalities than expected. Some studies have shown an increased rate of pregnancy, a decreased rate of miscarriage, and an increased rate of live birth following the use of PGD.

Before considering PGD, couples with a history of 3 or more miscarriages are encouraged to have their own chromosomes evaluated for the presence of inherited chromosome rearrangements, which can be done with a blood test. In approximately 5% of couples with recurrent pregnancy loss, one member of the couple is found to have a balanced chromosome rearrangement. A balanced chromosome rearrangement does not affect a person’s health, but it does greatly increase the risk for having chromosomally abnormal embryos, which will likely be lost in early miscarriage. If a chromosome rearrangement is found, there are specialized Preimplantation Genetic Diagnosis (PGD) methods that can be used to analyze embryos for the unbalanced rearrangement.

• Couples who have had previously unsuccessful IVF cycles

Data suggests that aneuploidy rates are higher in the embryos of couples who have experienced repeated IVF cycle failure. Some studies show an increased rate of pregnancy in these couples when PGD is used, although other studies show no clear indication that these couples benefit from PGD. In some couples, there may be reasons other than aneuploid embryos for unsuccessful IVF cycles.

PGD is only performed as part of IVF. PGD is usually performed on Day 3 after fertilization, when a single cell from each embryo is removed, sent to GSN, and tested. The embryos themselves do not travel –they stay at your IVF center. Results are available on Day 5 in time for a fresh embryo transfer.

Using a newer biopsy technique, PGD can also be performed on Day 5 by removing and testing a few cells from each embryo.  Embryos are frozen until test results are returned. They are then thawed and transferred in a future FET IVF cycle.

When embryo biopsy is performed on Day 3, all of the cells of the embryo are similar and are not yet separated into different cell types. One single cell called a blastomere is removed on Day 3. In a Day 5 biopsy, a cluster of two to ten cells is removed from the mass of cells called the trophectoderm, which is the tissue that will become the placenta Removing one cell on Day 3 or several cells on Day 5 for testing does not appear to disrupt or interfere with subsequent fetal development and has not been associated with an increased risk of birth defects. Babies born after PGD that include embryo biopsy have had a similar rate of birth defects as compared to all other babies in the general population.

Embryo biopsy in the absence of PGD has been shown in some studies to be associated with a reduced rate of implantation. However most doctors feel that if the biopsy procedure is correctly performed, aneuploidy screening more than compensates for this reduced rate of implantation resulting in equivalent or better implantation rates.

No other known adverse effects associated with embryo biopsy or PGD have been reported to date. However, as embryo biopsy is still a relatively new procedure the potential for unknown consequences to a live born baby cannot be entirely excluded.

GSN’s Parental Support testing requires parental DNA samples that are used as reference data for testing the embryo samples.  Array CGH does not use related reference data, but instead general control DNA that is unrelated to the embryo DNA. By using related DNA information, Parental Support has higher accuracy, and identifies the parental origin of chromosome abnormalities, uniparental disomy (UPD), and complete missing or extra sets of chromosomes.

GSN’s Parental Support testing is able to identify whether a missing or extra chromosome is maternal or paternal in origin. This can be important in looking for patterns of chromosome abnormalities which may indicate a parental chromosome rearrangement. Knowing if errors are maternal or paternal in origin can help couples decide about future steps in the IVF process, including consideration of egg or sperm donors.

Yes, because our testing process references genetic data from the parents, we automatically confirm that the embryo cells match the parent samples. In fact, we are unable to issue a report if the biological parents do not match the embryo cells that were sent.

In cases where a fresh transfer is planned, Day 3 biopsy should be performed. One cell is removed from each available embryo on Day 3 after fertilization and sent to Natera for testing. Results are made available to the IVF center the morning of Day 5 in time for a fresh transfer that day.

In Day 5 biopsy, a cluster of two to ten cells is removed from the mass of cells called the trophectoderm, which is the tissue that will become the placenta. Since embryos do not survive well outside of the mother’s uterus beyond Day 5 or 6, the embryos are frozen until results become available (5 business days from receipt of cells). Embryos with normal chromosome results may then be thawed and transferred. Not all IVF clinics perform Day 5 biopsies, so please check with your IVF center if you’re interested in more information about this option.

Natera recommends that you use intracytoplasmic sperm injection (ICSI) for fertilization during your cycle to eliminate the risk of sperm contamination; however, we do not require it. In several cases when ICSI has not been used, we have seen triploidy (a complete extra set of 23 chromosomes) of paternal origin. Since paternal triploidy is rare, we suspect that most of these cases are due to an extra sperm outside of the embryo that contaminated the biopsy sample.

There are many different factors that influence whether or not you will become pregnant during your IVF cycle. Natera’s current pregnancy rates, as reported by IVF centers, are as follows:

• For Day 3 blastomere biopsy with fresh transfer there is approximately a 56% pregnancy rate (defined as fetal heart beat seen on ultrasound at 6-7 weeks); this rate is slightly higher in patients aged 35 and younger and slightly lower in patients aged 36 and older.
• For Day 5 trophectoderm biopsy with Frozen Embryo Transfer (FET), there is approximately a 61% pregnancy rate.

Prenatal diagnosis in the form of chorionic villus sampling (CVS) or amniocentesis is strongly recommended to people who have PGD. Although highly accurate, PGD is not 100% precise. Although PGD has been performed for years, the technology is still considered investigational.

PGD also cannot detect chromosome mosaicism because testing is typically done on only one cell from the embryo, and mosaicism can only be detected by testing the chromosomes of multiple individual cells. Prenatal diagnosis can confirm that the baby’s chromosomes are normal.

No. There is a 3-5% chance in any pregnancy of having a child with a birth defect or mental retardation, regardless of any testing performed before or during pregnancy. Many of these conditions are not detectable prior to implantation or even during pregnancy. Parental Support detects the portion of birth defects caused by aneuploidy (extra or missing chromosomes) but does not identify other structural chromosome abnormalities, such as balanced translocations or small rearrangements of chromosome material. Also, as with all types of PGD, Parental Support does not analyze particular genes unless specifically requested, so it will not routinely identify single gene disorders like cystic fibrosis, muscular dystrophy, or Tay-Sachs disease.

Most cases of autism are not associated with chromosome abnormalities, and no form of aneuploidy PGD, including Parental Support, can screen for autism in embryos.

There are likely multiple factors that contribute the development of autism in any particular child. At this time, the majority of cases of autism in children have no identifiable genetic cause.

About 15-20% of children with autism may be found to have a gene mutation (a change in the code of one or more genes) that is thought to contribute to or cause the condition. If a family already has a child with autism who has been found to have a causal gene mutation, it may be possible to set up a custom Preimplantation Genetic Diagnosis (PGD) test to look specifically for this mutation in the embryo. Contact Natera at info@natera.com if you have a known autism-related gene mutation in the family and would like to explore PGD.