Growing Your Family with Fragile X Syndrome or Fragile X Premutation
Couples may find out that the female or the male partner has an expansion on the FMR1 gene, including the Fragile X premutation, commonly referred to as a “Fragile X carrier” or the full mutation referred to as “Fragile X syndrome.” Naturally, many questions arise.
Commonly asked questions include, What are my options for the future? How can I increase my chance of having a child without Fragile X? What are the options to test a pregnancy in the future?
Growing your family is not always a straightforward process, and depending on your personal, cultural, and religious beliefs, some options may not be the right fit for you. There are several ways to build a family when one of the partners has the Fragile X premutation or full mutation. Some of these options include:
1. Conceiving naturally and not doing any testing.
2. Conceiving naturally and testing the pregnancy via prenatal diagnostic tests.
3. Undergoing in vitro fertilization (IVF) and using:
- both partner’s genetic material (egg from female and sperm from male), testing any embryos in the laboratory, and implanting only unaffected embryos.
- a donor egg (if the female partner carriers the premutation or has Fragile X syndrome).
- donor sperm (if the male partner carriers the premutation or has Fragile X syndrome)
- a donor embryo, which would have no genetic material from either partner.
4. Choosing to adopt.
5. Choosing not to have children.
Let’s walk through each of these options together.
1. Conceiving Naturally and Not Doing Any Testing
You and your partner may choose not to have any type of genetic screening and testing for yourselves or your future child or children. This is your choice, you do not have to do any testing.
All carrier and genetic screening and testing are optional. If you change your mind, any screening or testing can be performed later in life at the recommendation of a healthcare provider. If you choose not to test yourself and your child’s physician is concerned about a potential genetic disease in your child, they can order necessary testing after the child’s birth.
2. Conceiving Naturally and Testing During the Pregnancy
There are two different methods to evaluate the genetic status of the fetus during pregnancy:
- Chorionic villus sampling (CVS)
Your healthcare provider will discuss and review the procedures, and possible risks, and answer any questions you and your partner may have.
Both procedures obtain tissue or amniotic fluid from the pregnancy to obtain DNA. The DNA is then analyzed to determine the genetic status of the pregnancy. It can test for the number of chromosomes and specific genetic disorders. These tests are commonly offered to women for reasons like advanced maternal age or a positive carrier screening test. You can speak with your healthcare provider about these options if you know your Fragile X status and would like to know the Fragile X status of the fetus.
Amniocentesis, sometimes called an “amnio,” uses a small sample (two tablespoons) of the amniotic fluid that surrounds the fetus. This fluid has fetal cells that can be grown and analyzed for various genetic conditions.
The procedure is usually performed between 15 and 20 weeks of gestation, which is determined by ultrasound or by the first day of the last menstrual period. Using an ultrasound, the healthcare provider inserts a very thin needle through the abdomen to withdraw the fluid from the uterus. The fluid is then taken to the laboratory to begin the testing process. For many women, the procedure feels like a blood draw, though some feel mild cramping in their uterus.
After the procedure, the woman is given care instructions regarding rest, travel, etc. The risks of the procedure include miscarriage, bleeding, cramping, and amniotic fluid leakage. The risk for miscarriage is approximately 0.1% to 0.3% when done by a skilled healthcare provider using ultrasound during your second trimester.
Your healthcare provider or a genetic counselor will help you understand your amniocentesis results. It may take a few weeks to receive your results.
CHORIONIC VILLUS SAMPLING (CVS)
Chorionic villus sampling requires obtaining a small sample from the developing placenta.
The placenta is usually the same genetically as the fetus, but there can be exceptions. Chorionic villi are small fingerlike projections on the edge of the placenta. The cells can be studied for chromosome abnormalities such as Down syndrome and FXS if the woman is known to have the Fragile X premutation or full mutation.
CVS is performed earlier in pregnancy than amniocentesis, usually between 10 and 13 weeks of gestation. It is also performed using ultrasound equipment.
There are two methods of withdrawing the sample, depending on the position of the placenta.
- If the placenta is behind the fetus, the healthcare provider inserts a thin tube through the vagina/cervix.
- If the placenta is in front of the fetus, a small needle is inserted through the abdomen, similar to amniocentesis.
Using gentle suction, the doctor removes a very small amount of chorionic villi for laboratory analysis. Some women feel cramping or pressure, while others do not find it uncomfortable. Like amniocentesis, there is a small risk of miscarriage (less than 1%). If performed earlier than 10 weeks gestation, there is an associated risk of limb defects.
3. Undergoing In Vitro Fertilization (IVF)
In vitro fertilization (IVF) is an assisted reproductive technology in which the ovaries are stimulated with hormones to produce multiple eggs, the eggs are retrieved and fertilized with sperm outside the body in a laboratory. Once the eggs are fertilized, they may or may not become embryos.
If they become embryos, you can choose to have them undergo genetic screening before any embryo transfers and pregnancy. The subsequent embryo transfer can happen the following month or the embryos can remain frozen for multiple years (e.g., for family building). Following the embryo transfer, you will wait about two weeks to take a pregnancy test.
Individuals considering IVF are encouraged to check with their insurance provider about coverage before initiating any services. Some employers may also offer employee assistance programs that support fertility services and adoption. Many IVF clinics also have service and financial navigators that you may be able to speak with.
RESOLVE: The National Infertility Association is a fantastic resource to learn about state-by-state coverage and how to advocate for improved employer benefits.
Preimplantation Genetic Testing
American College of Obstetricians and Gynecologists
CHOOSING A CENTER
You can explore fertility clinics nationwide and their respective success rates through the Society for Assisted Reproductive Technology.
You might consider asking the clinic the following questions:
- Have you heard of Fragile X?
- How much experience do you have with Fragile X testing?
- Do you have a genetic counselor on staff?
- What lab does your clinic use for embryo genetic testing?
- Do you have a financial counselor or consultant to help understand the cost/expense?
- How many “cycles” are typical for most patients?
- What are your success rates and failure statistics? Do you have this information specific to those individuals with Fragile X?
- What testing should I have done to have a better idea of our potential success chances?
- Do you have additional or alternative therapies that you recommend (e.g., acupuncture, dietary, yoga, supplements)?
- If applicable, how will my FXPOI impact this process?
- What are realistic expectations based on what you know about my or our health history?
STARTING THE IVF PROCESS
Before any egg retrievals or embryo transfers, you must have a fertility evaluation. For females, an ovarian reserve quantity of eggs is checked, and for males, sperm count and quality are assessed.
You will consult with a fertility specialist, likely a reproductive endocrinologist, on your goals. This is a great time to explain your Fragile X status and if it has an impact on your family planning.
Genetic pre-clinical workup (test development process): For those electing to pursue PGT-M to test for monogenic conditions (i.e., Fragile X syndrome), each partner’s DNA needs to be understood. To develop the custom test information (often referred to as a “probe”), DNA samples (blood or saliva) are collected from each partner to create a custom “fingerprint” associated with the genetic expansion. In some situations, additional DNA samples of family members may be requested.
Questions you may consider discussing during the consultation:
- Who in our family will be requested to provide DNA samples?
- What if the family member is unable to provide a DNA sample, will the accuracy be impacted?
- How long will the test development process take once the DNA samples are received?
- Is there an additional cost or fee for the test development process?
Many patients who are biopsying their embryos for PGT-M for a specific disease also choose to screen the same sample for the number of chromosomes, which is called “aneuploidy screening” (PGT-A).
Once the consultation and evaluations are complete, you will begin hormone medications to stimulate your ovaries before the egg retrieval.
The medications typically start on Day 1 of your cycle (the first day of your period). The medications are all injectable (e.g., shots) hormones that patients give themselves at home. Routine monitoring will occur leading up to the retrieval and includes blood draws to test your hormone levels and transvaginal ultrasounds.
Typically, you only ovulate one egg per cycle. Ovarian stimulation attempts to grow as many eggs as possible in a safe way, which may be uncomfortable. Tell your fertility specialist if you become uncomfortable or are in pain at any time in the process.
Your fertility specialist will advise you on any medications you will need and how to take them to prepare for the egg retrieval. You will have frequent appointments for monitoring while you take medication.
Once your fertility specialist determines your follicles — or the structures where an egg grows — are large enough, you will “trigger” them. This trigger is the last piece to help the eggs fully mature before retrieval. This trigger is usually a shot, and the timing of this shot is very important. Be sure you know the exact time you are supposed to take the shot before the egg retrieval.
After your trigger shot, you will be scheduled for your retrieval.
TIP Sometimes ovaries don’t respond to stimulation, which means your egg retrieval would be canceled. If this happens, don’t give up hope! Ask your fertility specialist about the cause or causes, and possible next steps.
Your retrieval is two days after your trigger shot. Egg retrievals are typically done under light sedation or anesthesia.
Once you are comfortable, your fertility specialist will use a transvaginal ultrasound to guide a small needle through the vagina into your ovaries. Using the needle, your fertility specialist will take the fluid and egg from each of your follicles. The fluid is then looked at by the embryologist, who can identify the egg or eggs under a microscope and will perform fertilization of the eggs in the lab.
A sperm sample will be used for fertilization and is typically collected on the day of the egg retrieval. Frozen sperm samples can be used, though fresh are preferred.
Once the egg retrieval is complete, you will be taken back to a recovery area. You may experience some cramping or spotting after the procedure, drowsiness, or fatigue, though you will likely feel back to normal in a day or two. Ask your fertility specialist about what to expect!
Some individuals need to go through the ovarian stimulation and egg retrieval process more than once. A few factors that may influence this process include your family-building goals, response to the stimulation, or how the embryos grow in the lab. Understanding your possible outcomes is a great discussion to have with your doctor before beginning IVF.
An embryologist will combine any mature eggs with sperm for fertilization. Approximately 70% of eggs will fertilize. Embryos are monitored for the next three to five days. The embryologist will then prepare an embryo for a fresh embryo transfer, freeze the embryos, or prepare the embryos for genetic screening (preimplantation genetic testing).
Sometimes additional processes may be used to support fertilization or implantation. Examples of these processes are intracytoplasmic sperm injection, or ICSI, in which the embryologist uses a single sperm and injects it into each egg; or assisted hatching, in which the embryologist helps the embryo hatch from its shell, which may help the embryo implant. These are not always necessary, recommended, or covered by insurance.
IVF (In Vitro Fertilization)
PREIMPLANTATION GENETIC TESTING (PGT) — Optional
PGT Testing Procedures: A few cells from each embryo can be sent for preimplantation genetic testing (PGT) for either monogenic disorders (PGT-M) or the number of chromosomes (aneuploidy) (PGT-A).
PGT-M is used to screen for a specific gene or genetic condition like Fragile X. PGT-M tests a single embryo for the condition for which you specifically want to be tested, it does not test for all possible genetic conditions. Having carrier screening ahead of time can help make sure the risk of other potential genetic diseases is known before IVF.
PGT-A does not screen for specific genes or genetic conditions like Fragile X. PGT-A assesses the overall chromosomal makeup of the embryo.
- If an embryo has 46 chromosomes — 23 from the female and 23 from the male — it is considered an euploid embryo.
- If there is an extra chromosome or is missing a chromosome, that embryo is considered an aneuploid embryo.
The chance that each embryo is euploid depends on the woman’s age. Discuss with the healthcare team what is the most appropriate testing option for you. There are challenges associated with conducting both PGT-M and PGT-A.
Should you choose to undergo PGT-M testing for Fragile X, they can select PGT-M with triplet repeat detection, which identifies both the full mutation (FXS) and the premutation of the FMR1 gene. These tests have their limitations, and you must discuss the risks and benefits of them with your healthcare provider.
One of the difficulties when attempting PGT for individuals with the Fragile X premutation is that some individuals have Fragile X-associated ovarian insufficiency (FXPOI), which can range from premature menopause to reduced ovarian functioning. This can make it difficult to stimulate the ovaries to make the eggs needed for PGT.
TIP Women with a full mutation are not at risk for FXPOI and have no known associated infertility.
The overall accuracy of PGT-M is >97%; therefore, diagnostic prenatal testing by CVS or amniocentesis is often offered later in pregnancy.
PGT Results: If you elect to complete PGT-M on your embryos, testing will assist with identifying embryos that have inherited an FMR1 expansion resulting in the full mutation or premutation. Once evaluation and testing have been completed, the fertility specialist or genetic counselor will discuss the results with you. The fertility specialist may offer recommendations and suggestions based on the PGT results, but ultimately the decisions moving forward are up to you and your partner.
Embryo transfers are either “fresh” or “frozen,” If you choose to do PGT, your embryos will be cryopreserved or frozen until the testing results are in. This can take 2-3 weeks. If you choose not to do PGT, you may be eligible for a fresh transfer, meaning your fertility specialist will schedule an embryo transfer a few days after your egg retrieval.
Both frozen and fresh transfers follow the same process. Most processes involve taking medications to prepare the uterine lining leading up to the transfer.
An embryo transfer does not require anesthesia and typically takes less than 10 minutes. Your fertility specialist will use a speculum and insert a catheter through your cervix into the uterus. The embryo will travel into your uterus through the catheter. You may experience mild cramping or spotting in the days following the transfer. You will typically be scheduled for a pregnancy test around two weeks later.
What about the remaining embryos? It is important to discuss your options for the embryos you may not be able to use with your fertility specialist. Your decision may vary according to personal beliefs and financial considerations and some options are not available in every state due to state law. Keeping an open line of communication with your partner and fertility specialist before and throughout the process is important in helping you to make the best decision for you. Working with a psychologist who specializes in fertility issues may also help. Your options may include:
- Embryo donation: Couples may choose to donate their fertilized embryos to other couples who are unable to produce embryos on their own.
- Donate embryos to scientific research: Couples may donate unused embryos to scientific research.
- Thaw and dispose of embryos: Couples may choose to thaw and dispose of their unused embryos utilizing their clinic’s resources.
- Do nothing, decide later: Embryos may be frozen and stored for a fee at some fertility labs. Other labs may require the patient to relocate their embryos to a commercial storage site until they have determined what option is right for them.
USING DONOR EGGS, SPERM, OR EMBRYOS
Some couples choose to use materials from a donor without the Fragile X premutation or full mutation. Couples can use either donor eggs, sperm, or even a donor embryo. This option may be especially helpful for females with the Fragile X premutation who have FXPOI and may struggle to develop many eggs of their own.
Using donor materials can also eliminate the risk of passing on Fragile X if that is of interest to you. However, if you wish to have a child who is biologically related to both the mother and father, this option does not meet those needs.
The process of utilizing donor eggs also utilizes IVF. The female recipient begins the process with medical tests for any infectious diseases, RH type, thyroid, general health screening, and so on. The egg donor goes through their screening, which includes hormone levels, genetic screening usually including FMR1 (Fragile X) screening, family history assessment, psychological consultation, and more. The recipient couple meets with a donor coordinator to discuss their criteria for a good match, and then, with the coordinator, selects an egg donor whom they feel would meet these criteria.
Following the donor screening and selection, the egg donor is given injectable hormones to stimulate her ovaries to produce multiple eggs. The eggs are retrieved from the donor at the optimal time (called “egg retrieval”), and then the eggs are fertilized in the laboratory by sperm from the recipient’s husband or a donor.
The embryos can either then be frozen for a future transfer to the intended parent’s uterus or their cycles can be coordinated for a fresh transfer. The intended parent usually stays on hormones for two months to support the early stages of the pregnancy.
4. Choosing to Adopt
Couples who wish to grow their family but do not want to use their genetic material, are unable to use their genetic material, or simply want to explore additional options, may choose to adopt. The adoption process can be lengthy, and there is never a guarantee that couples will be able to adopt.
Some couples choose to foster children, which can lead to adoption. Other couples may work with either a public or private agency to identify children who are eligible for adoption.
Speak with your local public agency or one or more private agencies to find the right fit. Public agency services may be free or very low cost and are potentially reimbursable.
Private agencies go through the same processes as public agencies but typically charge for their services. Do your homework. There are, unfortunately, groups and people who take advantage of couples in this space by charging fees up front and then not following through with services. Ask for references or to be connected with other families who they have worked with.
4. Choosing Not to Have Children
Some couples may choose not to have children. Growing your family is your choice, and if you decide it is not for you, that is your choice to make, no matter the reasons that inform your choice.