Can PGS improve IVF outcome?

So as we get ready for Halloween and all those cute little goblins and princesses let’s tackle the million dollar question: Does PGS improve IVF outcomes? The lunch debate between Munne and Hughes at the ASRM sought to discuss that issue. Basically, Dr. Munne presented evidence that in their hand IVF outcomes are better and miscarriage rates are lower. However, the improvement was modest and not the amazingly high pregnancy rates that one would predict. Dr. Munne also criticized the recent article from Europe in the New England Journal of Medicine that showed lower delivery rates after PGS. But still the question remains as to whether PGS is the Holy Grail (“I’ll ask him but I don’t think he’ll be very keen…you see he’s already got one”) of IVF.

Dr. Hughes presented data from a recent study of his that was very informative. In this study, Dr. Hughes analyzed embryo biopsies from PGD cases for single gene defects (like cystic fibrosis). All embryos that were biopsied were analyzed for aneuploidy and also DNA fingerprinting was done. The aneuploidy data was blinded so no one knew what it showed. Once a healthy baby was born, DNA fingerprinting allowed Dr. Hughes to go back and identify the exact embryo that resulted in the healthy baby.

So what did his data show…it showed that in 16% of the cases that resulted in a healthy baby, the aneuploidy screen would have suggested that the embryo was abnormal and should NOT be transferred! How is this possible? Read the Question of the Day from 100 Questions about Infertility and find out….Pretty scary thought for Halloween.

74. Can PGS improve outcomes after IVF?

PGS has been promoted as a means to improve the odds of a successful IVF cycle. However, a large-scale, randomized, controlled study performed in women older than age 37 failed to demonstrate an improvement in clinical outcome following its use. Although the use of PGS will likely decrease the rate of miscarriage resulting from aneuploidy (an abnormal number of chromosomes in the embryo), the overall delivery rate per IVF cycle initiated may not be increased with this technology.

For couples in whom the use of prenatal diagnosis and possible pregnancy termination are not an option, PGS may be appropriate. According to an October 2006 monograph produced by the European Society of Human Reproduction and Embryology (ESHRE), “Although widely used, PGS is still considered as an experimental procedure, and its clinical utility is not fully proven.” One limitation of PGS is that many embryos at the 6- to 8- cell stage of development are mosaics, meaning that some of these cells carry a normal complement of chromosomes while other cells are abnormal. During further embryonic development, the abnormal cells presumably end up relegated to the placenta while the normal cells produce a healthy embryo.

The high rate of mosaicism in cleavage-stage embryos raises a real concern about the accuracy of PGS. One respected geneticist has estimated a rate of misdiagnosis to be 20% with PGS. Approximately 17% of the time a normal embryo is incorrectly labeled as abnormal and discarded. Even more concerning is the 3% chance that an abnormal embryo will be labeled normal and then transferred to the uterus.

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Is PGD safe?

As Gandalf said to Frodo “Is it safe?” That is certainly an important question to examine. If we pursue PGD we certainly do not want to shoot ourselves in the foot.

First of all, how could PGD create a problem? Well there are several steps that could cause potential problems. The embryo biopsy could result in damage to the remaining cells in the embryo. The removal of 1/8th of the cells in the embryo could alter the development of the embryo. The biopsy of the embryo could result in an embryo that is less tolerant of cryopreservation (freezing). The testing on the embryo could be inconclusive or incorrect. Finally, the assumption that all 8 cells in the embryo are identical and thus representative of the reproductive potential of the entire embryo may be incorrect.

All of these concerns are reasonable and I will address them later but for now let’s see what is in the book...Here is today’s question of the day from the book that all Red Sox fans should buy ASAP: 100 Questions and Answers about Infertility.

73. How safe is PGD or PGS?

An estimated 5,000 cycles of PGD/PGS are being performed in the United States each year. Although the use of these techniques is clearly increasing, the number of PGD/PGS cycles continues to represent only a small fraction of the 100,000 IVF procedures performed annually in the United States alone. The rate of congenital anomalies and of pregnancy complications following PGD/PGS does not appear to be increased over the baseline measurements. On occasion, misdiagnosis may occur, so patients undergoing PGD/PGS are usually offered traditional prenatal diagnostic tests (chorionic villus sampling-CVS or amniocentesis) to confirm the results. The rates of misdiagnosis in PGD range from 1% to 9%. Embryos from which no diagnostic information is obtained are usually discarded rather than risk embryo transfer, although this policy varies from clinic to clinic. The other risks of PGS/PGD are the same as those associated with any cycle of IVF, including multiple pregnancy and OHSS.

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What is PGD/PGS?

What a difference a couple of weeks can make. Several weeks ago the Red Sox seemed doomed to another “close but no cigar” type of season and here they are in the World Series. Over October 12-16th the annual meeting of the ASRM was here in Washington DC. It is tough to have the meeting in one’s hometown as working while attending the daily meeting can be problematic…although not as problematic as going out at night to parties and then working the next AM. However, as a fairly boring the Eagle Scout straight arrow nice guy who prefers to be in bed a by 10 PM I really wouldn’t be able to comment about what went on after dark at the ASRM. But if you want to know if your RE behaved, please feel free to contact me and I can elaborate on all the juicy details.

One of the highlights of the meeting was a lunch debate between Santiago Munne, PhD and Marcus Hughes, MD, PhD on the topic of whether preimplantation genetic diagnosis (PGD) for aneuploidy (also known as preimplantation genetic screening (PGS)) will become standard of care in IVF. Both are excellent scientists, although I must admit that Dr. Hughes is, in my book, one of the smartest human beings on the planet. Over the next few blog posts I want to address the issue of IVF with PGD/PGS and after keeping you all (and my Mom) in suspense I will tell you about the outcome of the debate.

So please accept my humble apologies for being slow to post recently…it took me a while to recover from Club Luv at the ASRM (just kidding). Here is the latest Question of the Day from the book that is being promoted on WTOP here in Washington. How about some more 5-star reviews on Amazon ? (just thought I would ask).

72. What are PGD and PGS?


Preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) are techniques that provide diagnostic information concerning an embryo prior to its transfer to the uterus. The vast majority of PGD and PGS procedures are performed by removing 1 or 2 cells (or blastomeres) of a 6- to 8-cell embryo on day 3 of embryo culture following IVF. These cells are rapidly analyzed, and on day 5 the unaffected embryos are selected for embryo transfer. PGD was first performed in 1989 in an effort to avoid the transfer of embryos that carried serious genetic disorders (for example, cystic fibrosis). Thus couples who undergo PGD do not have infertility but rather are at risk for passing a genetic disease to their children. A wide range of single-gene and chromosomal disorders can now be diagnosed with PGD, including autosomal recessive diseases (e.g., cystic fibrosis), X-linked recessive diseases (e.g., hemophilia, Duchenne muscular dystrophy), autosomal dominant diseases (e.g., Huntington’s disease), and chromosomal rearrangements (e.g., balanced translocations). PGS is similar to PGD, but refers to screening of embryos produced in the course of fertility treatments. Thus couples who undergo PGS include infertile patients without an underlying genetic problem. PGS is performed in an attempt to identify those embryos that are genetically abnormal so that improved embryo selection will—ideally—result in improved pregnancy rates and lower miscarriage rates.

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How many do I put back?

On the INCIID bulletin board I am often asked to comment on how many embryos to transfer. It amazes me that anyone would value the opinion of the cyber-RE over their actual RE. This decision is too important to just gloss over and give it only a passing thought. Transfer too many and we have to deal with twins…or worse. Transfer too few and the next thing you know the patient is requesting records to zip off to the RE down the street. How easy things would be if the government mandated single embryo transfer…but although that works in countries with comprehensive government supported healthcare, it seems unlikely to occur in the USA. I am not a big fan of twins and would be only too happy to never have another twin pregnancy come out of our clinic, but when patients reach the point of embryo transfer they are willing to risk a lot to get that positive beta…even a multiple pregnancy.

So here is today’s Question of the Day from the book 100 Questions and Answers about Infertility that was written on my laptop that is currently sitting in a pawn shop in PG County waiting for the police to recover it (turns out you actually cannot buy stolen good legally…even if you get a receipt!).

54. How do I decide how many embryos to transfer?

Determining the number of embryos to transfer in an IVF cycle is a crucial decision that requires careful discussion between the patient / couple and the physician. The goal of every
treatment cycle should be the delivery of a full-term, healthy, singleton baby. Although transferring more than one embryo will increase the pregnancy rate, at some point transferring additional embryos merely serves to increase the multiple pregnancy rate without altering the overall pregnancy rate.

Several European countries have eliminated all discussion of how many embryos to transfer by mandating that all patients undergo only single-embryo transfers. Whereas elective (or mandatory) single-embryo transfer has been promoted heavily throughout Europe, it has not yet received widespread acceptance in the United States. One of the major disadvantages of single-embryo transfer is that it leads to a decreased IVF pregnancy rate from the fresh cycle. Proponents of single-embryo transfer claim that the potential reduction in the overall pregnancy rate is well worth the marked reduction in the twin pregnancy rate.

Twin pregnancies can be problematic because they are associated with higher rates of preterm labor and preterm delivery. Some couples, however, may desire twins or at least regard them as a neutral outcome. This view is especially prevalent among patients who are paying for the treatment themselves (rather than it being covered by insurance) and regard twins as a “two for the price of one” outcome. As noted in Question 53, the greatest risk to the health of children following IVF is the complications related to prematurity associated with multiple births. Despite the risks associated with multiple pregnancy, couples still tell us every day that they would “love to have twins.”

The ASRM has published guidelines for making the decision of how many embryos to transfer (see Table 4). Patients who fall into the excellent prognosis category should transfer only one or two embryos, whereas those with an exceedingly poor prognosis—because of the woman’s age or multiple failed IVFs, for example—may undergo embryo transfer of five or more embryos. The most problematic decisions concern those patients who fall between these two extremes. Couples who are paying out of pocket for IVF will often pressure their RE to be more aggressive in terms of the number of embryos transferred. Of course, the expense involved in caring for premature infants is many times greater than the cost of all of the fertility procedures used to initiate those pregnancies.

The financial costs are merely one part of the picture, as caring for patients with preterm labor or premature infants is also associated with a variety of emotional, psychological, and physical costs. If multiple pregnancies occur, a multifetal selective reduction procedure can be considered. This procedure is performed at approximately 10 weeks of pregnancy and involves injecting a salt solution into one or more of the gestational sacs. The overall pregnancy loss rate following this procedure is usually less than 5%. In patients who wish to avoid a triplet gestation (but who will not consider selective reduction), it is best to limit the number of embryos transferred to one or two.

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Is Possession 9/10ths of the Law?

Readers of this blog may recall that my MacBook Pro was stolen from my car while it was parked in my driveway on a residential street in Bethesda, MD. Like a complete idiot I had left it in my unlocked car overnight and like an even bigger idiot I had not password protected the computer (huge gasp of shock from the reader). Fortunately, the computer was fully backed up just 48 hours earlier and I successfully restored all of my files (including the photo of me in my Boy Scout leader uniform which I have mercifully deleted from the blog).

Last night my son, Seth, came running downstairs and asked me to check out the weird message on my iTunes account. On my iTunes account info page my name had been changed to Marvin Dixon and my phone number had been replaced by a number that I did not recognize. This was not the first time I had seen this name. On Wed night I had received an email that listed my email account but with the name Marvin Dixon, not my name…

So I called Mr. Dixon who informed me that he had indeed purchased a MacBook Pro from a local Pawn Shop and had no idea it was stolen. Didn’t he wonder why it had all those files still on it??? Nope, he just figured someone needed the cash and sold it to the Pawn Shop. He said that he had taken it to the Mac store and they had helped him enter his name into the computer and the .Mac account! I was so pissed off at Apple if this is true. I had called repeatedly to Apple to ask if the computer could be listed as stolen based upon the serial number so that if someone took it to the Apple Store then it would send up a red flag. Not possible I was told repeatedly.

So I called the police, having previously filed a report and gave them the information about the new owner. The officer was very polite. I then asked him what happens next. Well, if Mr. Dixon did indeed purchase it from the Pawn Shop then the computer is now his!! So can I ask the great legal minds reading this blog to comment on this statement? Is possession 9/10th of the law?

Meanwhile, how about IVF. Does it work? How well does it work? That is today’s Question of the Day from the Doctor now known as Marvin Dixon…

52. How successful is IVF?


Overall, the success rates for IVF have improved markedly since 1978 (when Louise Brown was conceived), but success rates vary widely depending on the couple’s infertility factors and the clinic performing the IVF procedure. Success rates for U.S. IVF clinics are published on the CDC’s website (http://www.cdc.gov/ART/index.htm). The standardization of clinic success rates evolved from 1994 passage of the Fertility Clinic Success Rate and Certification Act (the so-called Wyden law), which seeks to protect U.S. consumers from inflated IVF success rates. Importantly, many subtleties influence clinic-specific IVF pregnancy rates, including patient selection bias (that is, some clinics tend to treat tougher cases, so their success rates might be lower than those of clinics that take only routine cases).

For women younger than 34 years of age, most will achieve pregnancy within one to three treatment cycles; indeed, many succeed in their first attempt. For women older than 35 years, the success rates tend to decrease simply because the aging process affects the quality of these women’s eggs. For a detailed discussion of IVF success rates, couples should visit the website for the clinic where they are considering treatment. They should also discuss their specific likelihood of success with their reproductive endocrinologist. IVF pregnancy rates do vary by clinic, so patients should carefully scrutinize their chances for success at the particular clinic rendering treatment.

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Doctor Personality Issues

All doctors have different styles and as a patient I truly believe that you need to be comfortable with your physician. There is a level of trust that must exist between patient and physician and this relationship goes both ways. Some patients want to abdicate all decision making responsibility and others want to agonize over every minor point sending their RE emails several times a day.

Overall, I think that I have a pretty good rapport with my patients and thus I am puzzled by the fact that twice in as many weeks I have had patients comment to the nurses that I am the “mean” or “serious” doctor in the practice. These were Dr. D's patients and I must admit that I did not do any routines for these patients from Monty Python and the Holy Grail nor used any references from Star Wars in my interactions with them. Go figure. So for any of those patients passing through the hallowed halls of Dominion Fertility, let me know if I have somehow undergone a personality change. This has happened in the past….

During my 2nd year of residency at Stanford our first child was born and he was what is known as a “fussy baby.” Sleeping was not his thing and so when I was on call at the hospital my wife was awake all night at home. So when I got home after 36 hours on call she would hand me Seth and say “he’s all yours.” It got so bad that my fellow residents took up a petition for us to put him on rice cereal to end the madness. The medical students who had previously given me good ratings turned on me labeling me “the type of doctor that I hope never to become…”

So enough about me…back to IVF and when to use it. Here is the “Question of the Day” from the book written by your favorite mean and serious RE…

51. How do I know if I need IVF?

Not all patients need IVF or are good candidates for IVF. Thus the answer to this question can be determined only after you undergo a comprehensive infertility evaluation by your reproductive endocrinologist. Nevertheless, some situations clearly require the use of IVF. For example, women with absent or severely damaged fallopian tubes should be treated immediately with IVF. Likewise, IVF should be performed first if the male partner has very poor sperm quality. For other patients, the use of IVF may be less clear-cut, especially given that many different treatment options exist. In such cases, the doctor should discuss with the couple the pros and cons of each option, and then all parties should jointly decide on a treatment plan.

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