PGD and PGS: Genetic Screening Before IVF

Preimplantation Genetic Screening to Prevent Disease & Improve IVF Success

Woman in lab running a test
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Genetic screening technologies like PGD and PGS, when combined with IVF treatment, have made it possible to reduce the risk of passing on devastating genetic diseases, possibly reduce the risk of recurrent miscarriage, and possibly improve the odds of pregnancy success.

As with all assisted reproductive technologies, it’s important you understand which situations the technology is best used for, the possible risks, the costs, and what to expect during treatment.

You may see the acronyms PGD and PGS used interchangeably. They are both genetic screening technologies and both require IVF, but they are very different in why and how they are used.

What Does PGD Mean?

PGD stands for "preimplantation genetic diagnosis." The key word here is "diagnosis."

PGS is used when a very specific (or set of specific) genetic disease needs to be identified in the embryo. This may be desired to avoid passing on a genetic disease or used to choose a very specific genetic tendency. Sometimes, both are needed—for example, when a couple wants to conceive a child who can be a match for a stem cell transplant for a sibling but also wants to avoid passing on the gene that causes the disease requiring a stem cell transplant.   

PGD does not test a single embryo for all possible genetic disease. This is important to understand. So, for example, if an embryo does not appear to have the gene for cystic fibrosis (CF), that doesn’t tell you anything about any other possible genetic disease that may be present.

It only gives you assurance that CF is highly unlikely.

What Does PGS Mean?

PGS stands for "preimplantation genetic screening." PGS does not look for specific genes but looks at the overall chromosomal make up of the embryo.

Embryos can very generally be classified as being euploidy or aneuploidy. In a normal situation, the egg contributes 23 chromosomes and the sperm another 23.

Together, they create a healthy embryo with 46 chromosomes. This is called a euploid embryo.

However, if an embryo has an extra chromosome—or is missing a chromosome—it is called aneuploidy. Aneuploidy embryos are more likely to fail to implant or end in miscarriage. If implantation, pregnancy, and birth take place, aneuploidy embryos may result in a child with mental or physical disabilities.

For example, Down Syndrome can occur when there is an extra copy of chromosome 18 or 21. PGS can identify this before the embryo is transferred to the uterus. In some cases, PGS can identify the genetic gender of an embryo.

Comprehensive Chromosome Screening (CCS) is one technique of PGS that can identify whether an embryo is XX (female) or XY (male.) This may be used to avoid a gender-linked genetic disorder or (more rarely) for family balancing.

How Do PGD/PGS and Prenatal Testing Differ?

Both PGD and PGS take place during preimplantation. This is unlike prenatal testing, where implantation has already occurred. Prenatal testing can only be done if a pregnancy has been established.

Chorionic villus sampling (CVS) and amniocentesis can identify chromosomal abnormalities in an unborn fetus. When abnormalities are suspected during prenatal testing, the options are to either allow the pregnancy to continue or terminate.

This can be a difficult decision to make.  

Those who choose to continue the pregnancy face uncertainty and fear of what’s to come at birth. Besides worry about having a child with lifelong disabilities, they may face an increased risk of stillbirth. Those who decide to terminate the pregnancy face grief, possibly guilt, and the physical pain and recovery of abortion.   

Also, some people have religious or ethical objections to pregnancy termination, but are comfortable with genetic testing before embryo transfer takes place. That said, PGD and PGS are not guaranteed. Most doctors recommend doing prenatal testing in addition to PGD/PGS, just in case a genetic diagnosis was mistaken or missed.

Possible Reasons for Testing for a Specific Genetic Diagnosis With IVF

Here are possible reasons your doctor may recommend PGD (or reasons you may request it.)

To avoid passing on a specific genetic disease that runs in the family: This is the most common reason for PGD. Depending on whether a genetic disease is autosomal dominant or recessive, the risk of passing on a genetic disorder to a child may be anywhere between 25 and 50 percent.

In some cases, a couple may not otherwise need IVF to get pregnant, and may not be facing infertility. Their only reason for pursuing IVF may be for the PGD testing.

As mentioned above, prenatal testing can also test for genetic diseases, without the added expense, risks, and costs of IVF treatment. But since the only option is pregnancy termination (or continuing the pregnancy) after prenatal testing, this is unacceptable to some couples.

There are hundreds of genetic diseases that can be tested for, but some of the most common are:

To screen for translocation or chromosomal rearrangements: Some people are born with all 46 chromosomes, but one or more are not in the expected position. These people may be otherwise healthy, but their risk of experiencing infertility, having a pregnancy result in miscarriage or still birth, or having a child with a chromosomal abnormality is higher than average.

For couples that have a partner with a translocation, PGD can be used to help identify embryos more likely to be healthy.  

For human leukocyte antigen (HLA) matching, for stem-cell transplant: Stem-cell transplant is the only cure for certain blood diseases. Finding a match within the family is not always easy. However, PGD can be used to choose an embryo that both would be a stem-cell match (HLA match) and to possibly avoid passing on that same genetic disease affecting a sibling.

If an embryo can be identified that is both an HLA match, and a pregnancy and healthy birth take place, the stem cells needed to save the life of the sibling can be collected from the umbilical cord blood at birth.  

To avoid passing on a genetic predisposition for an adult-onset disease: A slightly more controversial use of PGD is to avoid passing on genetic tendencies that may result in disease later in life.

For example, the BRCA-1 breast cancer gene. Having this gene doesn’t mean a person will certainly develop breast cancer, but their risk is higher. PGD can be used to screen embryos for the BRCA-1 variant. Other examples include Huntington disease and early-onset Alzheimer disease.

Possible Reasons for General Genetic Screening (PGS/CCS) With IVF

Here are some common reasons PGS may be used with IVF treatment.

To improve the odds for success with elective single embryo transfer: A number of studies have found that PGS can help improve the odds of pregnancy and reduce the risk of miscarriage, when choosing elective single embryo transfer.

With elective single embryo transfer, or eSET, your doctor transfers just one healthy looking embryo during IVF treatment. This is instead of transferring two embryos at once, a technique that increases the odds for success but also carries with it the risk of conceiving multiples. Multiple pregnancies bring risks to the mother and babies' health.

Without PGS, the embryo is traditionally chosen based on how it appears. It’s been found, however, that embryos that don’t look perfect under the microscope can actually still be healthy. And embryos that look healthy may not be as chromosomally normal as they appear. PGS takes some of the guesswork out.

To identify genetic gender: Usually used when a genetic disease is gender-based, PGS can help identify whether an embryo is female or male. This can be a slightly less expensive way of avoiding a genetic disease than PGD.

However, PGS may also be used to help a couple have a child of a specific gender when they hope to “balance” their family. In other words, they already have a boy and now want a girl, or vice versa. This would rarely be done if the couple didn’t already require IVF for another reason.

In fact, the ASRM and American College of Obstetricians and Gynecologists (ACOG) are ethically against using PGS for gender selection without medical reason.

To reduce risk of miscarriage in women with history of recurrent pregnancy loss: Miscarriage is common, occurring in up to 25 percent of pregnancies. Recurrent miscarriage—having three or more losses in a row—is not. PGS may be used to help reduce the odds of another miscarriage.

The research on whether or not PGS can truly improve pregnancy odds for women with a history of repeated pregnancy loss is unclear. For couples that have a partner with a chromosomal translocation, or specific genetic disease that increases the risk of pregnancy loss or stillbirth, PGD (not PGS) may make sense.

However, for couples whose losses are not connected to a specific genetic tendency for pregnancy loss, whether IVF with PGS really can increase the chances of a live birth any more than continuing to try naturally is unclear. There may be a lower risk of experiencing miscarriage, but a healthy pregnancy and birth may not come sooner.

Currently, the American Society of Reproductive Medicine does not recommend IVF with PGS to treat recurrent miscarriage.

To improve odds of pregnancy success for IVF patients: Some fertility doctors recommend PGS along with IVF to theoretically increase the odds of treatment success in cases of severe male factor infertility, couples who have experienced repeated IVF implantation failure, or women of advanced maternal age. Some clinics offer PGS with IVF to all patients.

There’s currently little research to show that PGS will truly improve IVF treatment success when it’s not specifically indicated. Many studies that have found higher success rates are looking at live birth rates per embryo transfer—and not per cycle. This will always be higher than per cycle rates, because not every IVF cycle gets embryos to transfer. It’s difficult to discern whether there is a true advantage. More studies need to be done.

How Are Embryos Biopsied?

In order to do any genetic testing, cells from the embryo must be biopsied. The zona pellucida is a protective shell that envelopes the embryo. This protective layer must be broken in order to biopsy some cells. To break through, an embryologist may use a laser, acid, or glass needle.

Once a tiny opening has been made, the cells to be tested are removed either with suction through a pipette, or the embryo is gentle squeezed until a few cells come out through the broken opening. 

Biopsy of the embryo may be done three days after fertilization or five days. There are pros and cons to each.

Day 3 Embryo Biopsy: An embryo on Day 3 is known as a blastomere. It has only six to nine cells. It’s possible to do genetic screening on just one cell, but taking two is better.

One of the biggest advantages of doing a Day 3 biopsy is testing can be done in time for a fresh embryo transfer on Day 5 post egg retrieval. This means less wait time and lower cost (since you may not need to pay for a frozen embryo transfer.)

However, some research has found that biopsy of more than one cell at this stage increases the risk of “embryo arrest.” The embryo may stop developing and can no longer be transferred. This is rare, but still a risk to consider. Also, the risk of false positives and inclusive results are greater with Day 3 biopsy.

Day 5 Embryo Biopsy: A Day 5 Embryo is called a blastocyst. At this stage, the embryo has hundreds of cells. Some of these cells will become the fetus, others the placenta. The embryologist can take more cells for testing—usually taking between 5 and 8—which can allow for better diagnosis and fewer inconclusive results. The cells taken are ones destined to become placenta; the fetal cells are left untouched.

A disadvantage of Day 5 biopsy is that not all embryos survive in the lab environment for so many days, even otherwise healthy embryos.

Also, Day 5 biopsy requires the embryos to be cryopreserved until the results return. This means the woman will need to wait until at least the next month to do the embryo transfer. It will be a frozen embryo transfer cycle. This means additional waiting time and additional costs. There is also a risk that the embryos won’t survive the freeze and thaw.

However, only the strongest embryos tend to remain after this process. Those that survive and have good PGS results are even more likely to lead to a healthy outcome.  

What Is the Process for IVF With PGD and PGS?

There are some differences in how the IVF treatment cycle goes for PGD or PGS testing.

First of all, with PGD, the process may begin months before the actual IVF treatment. Depending on the specific genetic diagnosis needed, genetic testing of family members may be required. This is needed to create a gene probe, which is kind of like a map used to pinpoint exactly where the genetic abnormality or marker is.

PGS does not require genetic testing of family members and only involves testing embryos. During the actual IVF cycle, the patient experience of PGS and PGD are similar, even though the genetic technology happening in the lab differs. If you’re not familiar with conventional IVF treatment yet, read this step-by-step explanation first.

Where IVF with genetic screening differs from conventional treatment is at the embryo stage. Usually, after the fertilization, any healthy embryos are considered for transfer three or five days after the egg retrieval. With PGS or PGD, the embryos are biopsied on Day 3 (after egg retrieval) or Day 5. The cells are sent for testing. If the embryos are tested on Day 3, the results may get back before Day 5. If so, any embryos with good results can be considered for transfer that cycle. Extra embryos can be cryopreserved for another cycle.

However, as mentioned above (in the section on embryo biopsy), Day 5 biopsy may be recommended or preferred. In this case, the embryos are biopsied and then immediately cryopreserved. No embryos will be transferred during the IVF cycle in this case. Instead, they will remain “on ice” until results from the genetic testing come back.

Once results are available, assuming any embryos are considered transferable, the woman will take medications to suppress ovulation and prepare the uterus for implantation. At the right time, one or a few embryos will be thawed and readied for transfer.  

When a Day 5 biopsy and frozen embryo transfer cycle is chosen, treatment time may span two to four months (with a possible month rest/waiting period.)

Risks of PGD/PGS

IVF with PGS and PGD comes with all the risks of conventional IVF treatment.

In addition to those risks, anyone considering PGD/PGS needs to also understand these additional risks:

  • Live birth rates may be lower than those of age-matched peers. This is because some embryos won’t survive the process and some (or all) may come back with poor results.
  • With Day 5 biopsy, there's a slightly increased risk of identical twinning.
  • False positives and false negatives are possible. In other words, embryos that are abnormal may test “normal,” and healthy embryos may mistakenly be diagnosed as abnormal and discarded. For recessive disorders, there is a 2 percent risk of an embryo getting a normal result when it’s abnormal, and an 11 percent risk for dominant genetic disorders.
  • If all embryos come back with poor results, there may be none to transfer.
  • Inconclusive results may occur. Also known as mosaic embryos, this is when some cells appear chromosomally normal and others do not. Some studies have found that mosaic embryos may correct themselves and can lead to a healthy pregnancy and baby.
  • Cryopreservation and subsequent thawing can lead to the loss of otherwise healthy embryos.
  • Some otherwise healthy embryos may not survive until Day 5 post egg retrieval.
  • Biopsy of Day 3 embryos may lead to embryo arrest, where the embryo stops developing.
  • PGD/PGS is not foolproof, and a child with a genetic disease or disorder may still result. Prenatal testing in addition to PGD/PGS is recommended for additional assurance.
  • Good PGD/PGS and prenatal testing does not guarantee the child won’t be affected by physical or mental handicaps of other kinds.
  • Risk of miscarriage may be lower with normal PGS embryos, but there still remains some risk of pregnancy loss.
  • Waiting for results and needing to make decisions about embryos with inconclusive results can be emotionally difficult.
  • The technology is so new that we don’t know for sure what the long-term effect may be on the children born after IVF-PGD/PGS. However, early results look good. Two small studies found that these children are not at an increased risk of developmental delays. They have also had normal birth weights.   

How Much Does PGS/PGD Cost?

IVF is already expensive. Adding on the cost for PGS or PGD raises that price tag even higher. On average, PGD/PGD adds on between $3,000 and 7,000 to IVF treatment. Your costs for one IVF cycle with PGS/PGD may be between $17,000 and 25,000.

On top of this, you may need to pay for a frozen embryo transfer (FET) cycle. This will be an additional $3,000 to 5,000. Sometimes, patients want to plan the FET cycle for immediately after the IVF cycle. This way, as soon as the results of the genetic screening come back, they can transfer any normal embryos without waiting an additional month.

However, a possible problem with this approach is that if there are no normal embryos to transfer, some of the FET costs will have been wasted. Any fertility drugs taken to suppress ovulation and prepare the uterus for implantation will have been taken without reason.

Waiting an additional month can be emotionally difficult, but may financially make more sense. With PGD, you may have expenses beyond the fertility treatment itself. PGD sometimes requires genetic testing of family members, and those costs won’t be included in your fertility clinic’s price quote and may not be covered by insurance.

A Word From Verywell

Genetic screening has helped families with genetic disease or chromosomal translocations have a better chance of having a healthy child and avoiding passing down devastating illnesses. Genetic screening has also helped doctors improve embryo selection in elective single embryo transfer cycles.

Whether PGD/PGS can truly improve live birth rates beyond these situations is unclear. The technology is still rather new and constantly evolving. Using PGS to improve live birth rates in IVF when the technology isn’t specifically indicated is controversial.

Some doctors claim to see improved success, while others question whether it’s truly worth the additional costs and risks. Some think it should be offered to every IVF patient; others believe it should be offered rarely, in very specific cases.

It’s possible that PGS can help avoid transferring embryos that would have inevitably ended in miscarriage. However, this doesn’t mean the couple wouldn’t eventually have had a healthy pregnancy result with subsequent frozen embryo transfers (FET) from the same cycle.

For example, let’s say a couple gets three strong embryos. Let’s say they do PGS and discover two of the embryos are normal. One or two are transferred, and let’s say pregnancy occurs in one or two cycles. Now, let’s say that same couple decided not to do PGS, and happens to transfer first the embryo with the chromosomal abnormality. That cycle will end in miscarriage. But they still have one or two more embryos waiting to be thawed and transferred, and are likely to get a healthy baby from one of those embryos. (In a best odds situation, of course.)

Currently, the research says the odds of live birth are similar in each situation—with and without PGS. But there is an emotional cost to experiencing miscarriage. PGS does not eliminate the odds of loss—though it does seem to reduce that risk.

Only you and your doctor can decide if IVF with PGD/PGS is right for your family. Before you decide, make sure you understand why your doctor recommends this assisted reproductive technology for you, the total costs (including cryopreservation and FET cycles), and the potential risks.

Sources:

Forman EJ1, Tao X, Ferry KM, Taylor D, Treff NR, Scott RT Jr. “Single embryo transfer with comprehensive chromosome screening results in improved ongoing pregnancy rates and decreased miscarriage rates.” Hum Reprod. 2012 Apr;27(4):1217-22. doi: 10.1093/humrep/des020. Epub 2012 Feb 16. 

Practice Committee of Society for Assisted Reproductive Technology; Practice Committee of American Society for Reproductive Medicine. "Preimplantation genetic testing: a practice committee opinion." Fertil Steril. 2008 Nov;90(5 Suppl):S136-43. doi: 10.1016/j.fertnstert.2008.08.062.

Schattman,  Glenn L; Xu, Kangpu. Preimplantation genetic screening. UpToDate.com.

Schattman, Glenn L. Preimplantation genetic diagnosis. UpToDate.com. 

Sermon K1, Capalbo A2, Cohen J3, Coonen E4, De Rycke M5, De Vos A6, Delhanty J7, Fiorentino F8, Gleicher N9, Griesinger G10, Grifo J11, Handyside A12, Harper J7, Kokkali G13, Mastenbroek S14, Meldrum D15, Meseguer M16, Montag M17, Munné S18, Rienzi L19, Rubio C20, Scott K21, Scott R22, Simon C23, Swain J24, Treff N22, Ubaldi F19, Vassena R25, Vermeesch JR26, Verpoest W6, Wells D27, Geraedts J4. “The why, the how and the when of PGS 2.0: current practices and expert opinions of fertility specialists, molecular biologists, and embryologists.” Mol Hum Reprod. 2016 Aug;22(8):845-57. doi: 10.1093/molehr/gaw034. Epub 2016 Jun 2.

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