Risks of PGD
When we think of technology and science we typically do not think about what can go wrong, we believe that technology and science is the way of the future and there is not a lot of risks involved. In our minds, technology is solid, foolproof and can be trusted. For this reason, some experts in the field of PGD worry that patients may not fully grasp the potential risks involved in PGD. In a New York Times article, Dr. Hudson, the director of Genetic and Public Policy Center at John Hopkins University, interviewed PGD patients to see if they understood the potential risks and concluded that "while the information had been transmitted, it was not received (1)."
With PGD, there is a phenomenon called mosaicism. This phenomenon occurs when the eight cells that make up the early embryo are not identical. Therefore, if PGD is performed and the biopsied cell is deemed normal, there is still a potential risk that the other cells in the embryo could be defective. Mosaicism happens in about 30% of embryos (1). Dr. Santiago Munne, director of Reprogenetics, reports that about 4% of PGD will be misdiagnosed because of mosaicism and maybe 1% more are misdiagnosed due to technical error (1). According to Dr. Munne, his clinical error, which is when a defective embryo is implanted and thrives, is 6/5,000 cases. Of the 6 that are misdiagnosed and implanted, one spontaneously miscarried and the rest of the pregnancies were terminated. Another PGD doctor reported rates of error for single-gene testing. Of 250 babies, 5 were misdiagnosed; 2 were missed because of technical errors and 3 were because of human error - transferring the wrong embryos (1). Do these statistics and risks factors change your mind about PGD? Let's walk through an example in which PGD was unsuccessful.
- PGD Gone Wrong: Jordan Flynn was born with a rare genetic blood disorder called Fanconi Anemia (FA). With FA, Jordan has a 700-fold higher risk of getting cancer than other children. The disease will likely leave Jorden with some type of cancer, and without a bone marrow transplant the life expectancy for Jordan, an FA patient, is 20 years old (2). Similar to the Trebing case, the best hope for Jordan was to have a bone marrow transplant from an exact match sibling. The Flynn's decided to take the route of IVF/PGD to create a savior sibling for Jordan. During the PGD process they were given results that of the 4 viable embryos, 1 was disease free and an exact match with Jordan, another had a 99.9% chance of being disease free and an exact match with Jordan, and the last two were either diseased or not a match to Jordan (3). The Flynn's decided to implant the 2 embryos that were a match for Jordan. They ended up with a set of twin girls. After running blood work on the twins, it turned out they both had FA, just like Jordan. The devastating news still haunts Ms. Flynn till this day. She feels responsible for bringing two more innocent children into this world with FA (3). Currently, the Flynn family has placed the three girls on a bone marrow registry with hopes that they can find an exact match.
Below are pictures of Jordan, the twins and their brother.
Possible Safety Concerns of IVF/PGD
First, we will discuss safety issues for women who undergo IVF/PGD. With the use of IVF, hormones are given to these women in order to stimulate ovulation and in doing is correlated with a possible increased risk of an ectopic pregnancy (where the fertilized egg or embryo attaches to anything other than the lining of the uterus) (4). With IVF about 2-5% of clinical pregnancies are ectopic (5). On the other hand, in pregnancies without IVF, 1 out of 60 pregnancies may be ectopic (6). Another concern is in order to increase the probability of a successful IVF, more than 1 embryo is implanted in the uterus for each cycle resulting in an increased chance of multiples (twins, triplets, sextuplets…Jon and Kate plus 8). These women carry increased risk of pregnancy complications that may affect their health and the health of their unborn children (4).
Next, safety issues of PGD children. Now, this topic has some controversy between experts regarding the possible long-term effects of children conceived by PGD. Some individuals believe that all babies born from PGD should be followed-up regularly to assess for any long term adverse effects that this technique may possess. As we have already introduced in previous posts, PGD was first introduced in 1990, and from its first use to 2005, it was estimated that 1,000+ babies were born worldwide from PGD. One of the UK centers offering PGD follow their PGD children regularly from 2 months of age until they are 5 years old and therefore questioned why other centers utilizing PGD are not upholding the same practice. Some experts strongly encourage close follow-up as they believe that PGD is still a fairly new procedure and like Dr. Siobahan SenGupta, from University College London, states, “it appears to be safe so far…but only time will tell” (7). On the flip side, others believe PGD is safe. For instance, the Reproductive Institute of Chicago studied 754 infants born after IVF/PGD pregnancies and the results showed that these children did not have increased incidence of birth defects than those born from natural pregnancies. However, we were unable to find information about possible long-term effects that PGD children may develop. We attribute this lack of data possibly due to the lack of regular check up of PGD children and also due to the current confidentiality legislations that prevents HFEA (Human Fertilization and Embryology Act) from distributing data on PGD children to the interested parties and specialists (7).
Interesting tidbit: In 2005, an experiment showed that those embryos that were deemed ‘defective’ (possessed abnormalities) detected via PGD were able to correct the defects as they matured. In this experiment, it was noted that half of the cells in the ‘defective’ embryos became normal by the blastocyst stage. This implied that the ‘defective’ embryo may be a source for embryonic stem cell donation and some of the embryos discarded as being defective could have potentially developed into a healthy fetus (8).
In the next section we wanted to give you more detailed information on bone marrow transplants and the complications and risks involved.
411 on Bone Marrow Transplant
Quick overview of bone marrow transplant
- The procedure of transfusing healthy bone marrow stem cells to the patient.
- Before transplantation of the new bone marrow cells, the patient undergoes high-dose chemotherapy and/or radiation to destroy dysfunctional bone marrow. Upon destruction of the patient's bone marrow, the healthy stems cells are transfused (transplanted) into the patient with the hopes that it will continue to produce new, healthy cells.
- Bone marrow is spongy, fatty tissue that contains stem cells found inside certain bones. These stems cells develop into red blood cells, white blood cells, and platelets (don't know what these cells are? Just know that, these cells are all very important and are essential players in our bodies).
How do you get bone marrow stem cells from the donor? There are 2 options:
1. Bone marrow harvest = minor surgery under general anesthesia, where a needle is directly inserted in the donor’s hip bones to retrieve the bone marrow stem cells.
2. PBSCT (Peripheral Blood Stem Cell Transplant) = a more non-invasive technique, in which stem cells are retrieved through a process called apheresis (kind of like a transfusion). Apheresis is where blood is removed either through the donor's arm vein or through the use of a central venous catheter (a tube placed in a vein in the donor’s neck, chest, or groin area). The blood then goes through a machine that separates the stems cells from the donor’s blood. About 4 or 5 days before apheresis, the donor has to have an injection that will stimulate the increase of stem cells in their blood stream (10).
After bone marrow transplantation, what are some possible complications?
- Inflammation/sores in the mouth
- Graft failure, when the new stem cells do not produce new cells.
- Graft vs. host disease (GVHD), when the donor’s cells attack your body.
- In children, may experience delay in growth.
Problem, Frequency, %
Renal dysfunction (Parikh, 2002), >50%
Cataracts (Aristei, 2002), 20-50%
Chronic GVHD (Stem Cell Trialists' Collaborative Grp, 2005), 20-50%
Endocrine dysfuntion, 20-50%
Infertility (Sarafoglou, 1997; Dann, 2005), 20-50%
Delayed sexual development, 20-50%
Dental problems (Vaughn, 2005), 20-50%
Psychosocial stress (Gruber, 2003), 10-30%
2ndary malignant neoplasms (Ghelani, 2005; Shimada, 2005), <20%
Cognitive disorders (Simms, 2002), <20%
Avascular necrosis of hips and other joints (Stern, 2001), <20%
Ventilatory dysfunction, <20%
*50-100% very common, 20-50% common <20%>
Judy: This week we wanted to provide some background information on IVF, PGD, bone marrow donation and transplantation. Hopefully, you feel as if we didn't let you down on that objective! Anyhow to my conclusive thoughts! First, I believe that it should be known that with all scientific/medical procedures, there are pros and cons, benefits and risks because let's face it, nothing is perfect. Therefore, parents who elect IVF/PGD procedures for the creation of a 'savior sibling,' would assess the pros and cons of their situation and would only decide to go forward with the procedure if they believed in the end, the benefits outweighed the risks. Also, I believe that PGD appears safe thus far, with no indications of harm in the children developed with this technique. It has been 19 years since PGD was first utilized and from our research, we did not find any data proving increased risks of birth defects or long-term effects on PGD children. I know we stated above that a possible hinderance of such data may be due to upholding patient's confidentiality but I believe if something profound arose in PGD children, media would be all over it. I do understand that further research on PGD children would be beneficial but if in the future they were diagnosed with an illness, how would it be differentiated that it was due to PGD vs high-dose chemotherapy and/or radiation therapy vs genetics vs any other possible causes?
Lili: Sorry for the long post you guys! We wanted this week to be about risks and safety issues behind procedures that are involved in IVF/PGD and savior sibling cases. First, I wanted to talk about the thought that most of us have that science and technology is 'foolproof.' Isn't it crazy how we trust science and technology so easily? How many times have we trusted the results of a blood test or a chest x-ray without giving it a second thought? Although we are probably told about the % error in many of the procedures performed, we often choose to believe that technology will pull through, and it usually does...but, after reading about the Flynn family and the outcome of their story, it brings things back into perspective. The example of the Flynn family and the phenomenon of mosaicism reinforces my thoughts that despite what man can do, we can not completely defy nature. As for safety issues with PGD babies in the future, it seems that there is not enough data collection or incidences to be of concern. From what we researched, if there is any defect in a PGD baby, it is presented early in the pregnancy or when the child is born.
Regarding the bone marrow transplants, we wanted to give you statistics and make sure that you understood that the procedure is complicated. The process is more than just taking bone marrow from a savior sibling and putting it into the ailing child and all is well. We see the success story in the Trebing case but there have been unsuccessful stories as well. Keir Zangrando was born with Diamond Blackfan Anemia just like Katie Trebing. After his bone marrow transplant Keir's organs started to breakdown and soon after, he passed away. In a Newsday article, Ms. Zangrando comments that she knew that a transplant was going to be tough, but she "thought the odds of something going wrong were very, very remote (11)." Again, here we see that people often do not understand the magnitude of what risks mean...risks/complications means that it CAN happen to you. For me personally, I was swept away with the thought that technology has given me the option that if I had a child with a rare disease such as Katie, Jordan, and Keir, I would be able to create a savior sibling. But after reviewing the unsuccessful stories, the option of creating a savior sibling or doing a bone marrow transplant isn't just a 'yes' or 'no' question anymore...it's more like...are you willing to take a risk of doing harm to your sick child/PGD child every step of the way to potentially save your sick child?
1. Laurie Tarkan. Screening for Abnormal Embryos Offers Couple Hope After Heartbreak. Available at: http://www.nytimes.com/2005/11/22/health/22gene.html
2. Jeannie Blaylock. Local Family Has Five Children, Three Facing Cancer. Available at: http://www.firstcoastnews.com/news/local/news-article.aspx?storyid=33355
3. Doreen Flynn. Our Personal Journey with PGD. Available at: http://www.fanconi.org/pubs/Newsletters/Family/FN42.pdf
4. Reproductive Health Technologies Project. Preimplantation Genetic Diagnosis. Available at: http://www.rhtp.org/fertility/pgd/default.asp
5. Advanced Fertility Center of Chicago. Tubal Ectopic Pregnancy and Fertility Problems. Available at: http://www.advancedfertility.com/ectopic.htm
6. American Pregnancy Association. Ectopic Pregnancy. Available at: http://www.americanpregnancy.org/pregnancycomplications/ectopicpregnancy.html
7. BBC News. Baby gene tests safety ‘unchecked.’Available at: http://news.bbc.co.uk/2/hi/health/4481839.stm
8. BioEdge. A second look at PGD. Available at: http://www.bioedge.org/index.php/bioethics/bioethics_article/a_second_look_at_pgd/
9. Girindra G Raval, John R Wingard, and Paulette Mehta. Bone Marrow Transplantation, Long-Term Effects. Available at: http://emedicine.medscape.com/article/989518-overview
10. National Cancer Institute. Bone Marrow Transplantation and Peripheral Blood Stem Cell Transplantation. Available at: http://www.cancer.gov/cancertopics/factsheet/therapy/bone-marrow-transplant
11. Newsday. Losing a Battle With the Disease. Available at: http://www.newsdayinteractive.com/diamond-blackfan-anemia/main.html