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Trends in Pre-implantation Genetic Diagnosis

So what are the new developments increasing interest in PGD?

 

The first is that there is more laboratory expertise on growing the embryos to blastocysts (see blog on blastocyst). These are embryos that have grown not 3, but 5 days in the lab.  As the embryo grows with time, the total number of cells increases from 6-8 to 30-60. Because the cell number is much higher, we can more safely remove more than on cell, maybe 3-5 cells. All of that extra DNA helps us reach much more accurate results.

 

The second has to do with the way we test the DNA.  The DNA amplification techniques have improved, as have the techniques for identifying important areas in the DNA.

 

An advantage of blastocyst biopsy is that in a good blastocyst, we can tell by looking which cells will be the embryo (the inner cell mass) and which will be the placenta (the trophectoderm- thus the term trophectoderm biopsy, also called TE biopsy for short).  Naturally, at the time of the biopsy, it is the placental cells we take as not to interfere with the fetal cells. Taking a few extra cells from the placenta is much less harmful than taking cells needed for the fetus.

 

Another advantage of performing the biopsy on day 5 is that mosaicism is much less of a problem in a blastocyst. (The last blog explains mosacism), The cells we get on day 5 more accurately reflect the DNA status of the embryo as a whole.   We are not sure why mosacisism is less of a problem on day 5, it may be that it’s common for an embryo to start off with some abnormal cells, but with time the normal cells outgrow the bad ones.

 

One downside to TE biopsy is that in most cases, the results of the biopsy take 1-3 days to process. We do not want a day 5 embryo growing extra days in the lab waiting for the results. Therefore, we usually freeze the blastocysts just after the biopsy, get the results a few days later, and then have the patient come back the next month for a thaw cycle.  This gives the patient a one month delay, which may or not be an important factor, depending on the expectations of the patient.  There are some programs that offer same cycle PGD biopsy and transfer, but usually those women with only the fastest growing and best looking are candidates for the same cycle process.

 

Patients are naturally concerned about embryo freezing, as is it is mostly true that embryos in a frozen cycle have lower pregnancy rates than when the embryos are transferred when fresh.  However, there may be some very explainable reasons why freezing normal blastocysts may not be problematic.  In a standard fresh cycle, the best embryos are transferred. While the extra embryos may look very good, the best ones go back originally, leaving the left overs for the frozen cycle, and this could explain the lower rates.  In a PGD cycle, even the best embryos are frozen, upping the odds for a successful cycle after the thaw.  Also, at least from what I have seen, normal embryos seem to thaw and freeze very well. So if you know you have a good one in the freezer odds are good that it will survive the freeze and thaw and have good potential for success.

 

In addition, freezing techniques have really blossomed in the past few years.  Most programs have moved to vitrification (the fast freezing method), and embryos do have better outcomes when preserved this way.

 

On top of all of this, there are some doctors who believe that all embryos, even without biopsy, should be frozen. There is the revival of an old theory that the endometrium of an IVF cycle is not ideal for implantation, possibly due to excessive estrogen levels caused by the fertility drugs. Others feel that the relationship between the timing of ovulation and embryo transfer is altered with IVF, lowering the ability of the embryo to implant.  I’m not so sure about theses theories, but I am raising the point here to say that a frozen embryo cycle is not necessarily a bad thing.

 

There are still a few more points about PGD that I will go over next time.

 

Thanks for reading, and don’t forget the disclaimer 5.17.06

 

Dr. Licciardi

 

References:

  • Braude P. Preimplantation diagnosis for genetic susceptibility. N Engl J Med 2006; 355(6):541-3.
  • Gutiérrez-Mateo C., Colls P., Sánchez-García J., Escudero T., Prates R., Wells D., Munné S. Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos. Fertil Steril. 2011; 95: 953-958.
  • Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006; 25(1):CD005291.
  • Munne S, Fischer J, Warner A, Chen S, Zouves C, Cohen J, Referring Centers PGD Group. Preimplantation genetic diagnosis significantly reduces pregnancy loss in infertile couples: a multicenter study. Fertil Steril. 2006; 85(2):326-32.

 

How to Find a Good Fertility Doctor

So you’ve been trying to get pregnant and it’s taking longer than you think it should. Now what? Sounds simple, you probably have a local gynecologist who you have been seeing for your checkups. Why not start there?

This may not be a bad idea at all. A general gynecologist could quite possibly be a very good fertility start. She has your history and may be conveniently located. But how can you tell she is good?

It boils down to 2 things: diagnosis and treatment.

Let’s start with diagnosis. If you have been trying 6-12 months, and you doctor says relax and try for 6-12 more months, relax your relationship with him. Of course he will occasionally be right and some people will be successful by just hanging in there, but most following his advice will still not be pregnant, and will be that much older.

Even if you want to wait, you should strongly consider at least having some basic simple testing. You can keep trying on your own as the testing proceeds, but at least you will acquire some important information. Once you get some answers, you will have the power to decide how to proceed.

Now what tests are we talking about? The gold standards are the HSG (hysterosalpingogram), semen analysis, and day 2 or 3 blood testing for FSH and estradiol (estrogen). All of these tests can be finished within a few weeks, and within that time you will have your bundle of information. Now some of this is a little simplistic because many of you have very complicated problems, but most people just starting out do not. And if the testing is systematic and is done quickly, you will all be on the right track.

You do need someone good to read your HSG. Many doctors will not look at your films; they will just read the report. This becomes less material when the report is normal, but much more significant when the report is abnormal. If you are told its normal, odds are it is. However, if you are told it’s abnormal, then you may need to take things one step further, usually by getting a second opinion, preferably with an RE. If you are told it’s normal and you continue without conceiving, you should have someone else have a look at it.

That’s the basic testing, sounds simple and it is.

What about the treatment side? For example, let’s say the HSG really is abnormal and you are told you need surgery on your uterus or tubes? Who should do your surgery? Your GYN or an RE? Many generalists are excellent surgeons, and some REs are terrible.

How do you know where to go for quality surgery? And let’s extend the question to “How do you find any good doctor?” Whether it’s a generalist or Reproductive Endocrinologist, how do you know who is good?

This is one of the most difficult questions in medicine. I would start by doing some of your own investigation.

What about those best doctors lists? This could be a good place to start because many doctors on those lists are good. However if you show a list to a good doctor who is very familiar with the people listed he will really wonder how some of them made it on. And I don’t know too many fertility doctors that are not on the “Best Doctors in America” list. That’s not a list of the super-best doctors in America, it’s a complication of all if the doctors who are on the best local doctors lists. So there is no cut to make the America list. Most of those lists give a high priority to chairmen and division directors, again most of whom are good, but holding one of those positions is not an automatic for quality. Some lists are assembled through other doctors voting, and some of that could be politically biased.

You may have local infertility organizations that could make suggestions. This is tough because although I think these groups do an excellent job, I have been involved with at least one group who referred to their biggest supporters. But it might be good to at least find out which doctors are on their list.

What if the doctor is in all the medical societies? Medical societies are very important organizations that provide education and networking, but unless you have a criminal record, almost all societies allow members in. So you will see most doctors with impressive lists of their fancily named societies, but membership is usually about paying your dues and getting your certificate. There are usually no entrance criteria that represent quality control.

What about board certification? There is no excuse not to be boarded in OBGYN. Most of us are. What if you are going to a specialist, does he need to be boarded in Reproductive Endocrinology? This is usually important but there are some excellent physicians who have good reasons for not being boarded in RE. Maybe they are young and are waiting to become eligible. Maybe they are a little older and trained before getting certified was the thing to do. I would say that if your doctor is not, you need to carefully evaluate other criteria.

Does it matter where she did her training? Again hard to say, but better programs are more likely to turn out better physicians. Some of this may have to do with recruitment. The places with the best training reputations can more easily recruit the smartest and most caring people. So just by getting the best, they will turn out the best. The problem for you is knowing which training programs are the best. There are many renowned institutions that just have bad programs. It’s not uncommon to have a hospital with a great program in one specialty and a very bad program in another. And sometimes things change quickly within a program, so the training can become worse before the reputation changes. Magazines do publish the lists of top hospitals, and I don’t think there are many bad places that make those lists. However, there are many excellent places that don’t get the nod.

Nurses can be a good referral source because they see the doctors work every day. But a referral from a nurse may not be a slam dunk. I have seen nurses refer to their better friends, or to the doctor who is popular because he frequently brings in pizza.
Nurses know who operates the most, but not about their daily functioning and this brings us to the next point.

Is a doctor who operates at high volume the best surgeon for you? Maybe. A doctor who operates frequently may be really wonderful and have a massive referral base that keeps him in the OR frequently. They can be more experienced and confident and have fewer complications. However, some busy surgeons are busy because, for whatever reason, they over-operate. And some of these doctors have not gained from their experiences and maintain a higher complication rate. They may feel their procedures are indicated, but others may not. Getting back to the nurse, he sees what’s happening in the OR but he does not know about how the patients have been worked up and how they are followed after surgery.

There is one good trick that only works in a teaching hospital: ask a resident. No one knows the skills and limitations of your doctor better than a resident. The resident is in the hospital all day long and is involved with the workups, surgeries and recoveries. They are constantly communicating with your doctor. And believe me the residents have very strong opinions about each of the doctors they work with. Now it is hard to get hold of a resident, but ask around, may be a friend of a friend knows one. Plus, many hospitals have departmental web sites that list the residents, and some may list contact information. Because they are young, tired and stressed, sometimes the residents are a little too opinionated, and they may know about some of the doctor’s personal issues that don’t affect you. If you have a doctor and want their opinion, you don’t need to hear the doctor is the best of the best. You do want to hear that she is solid, not that she is below average or worse.

What if your only source is your friend who became pregnant after seeing the doctor she recommends to you? This is not enough at all. Many questionable doctors get some of their patients pregnant. It doesn’t mean that they are good. Just like there are some of the best doctors who just can’t be successful with everyone. This is probably one of the most common ways couples find fertility doctors, but it is the least reliable. So if you are told about a doctor, use other sources to validate the person.

Check the available medical misconduct sources in your state. Your doctor should not be listed there. There is also the National Practitioner Database, but information about specific doctors is not available to the public. The database is viewed by hospitals and insurance companies. In addition to misconduct, it lists the cases where a doctor was sued. Even the most excellent doctor can have a few things listed; it’s the nature of the beast, the way of the world. Most doctors are non-malicious hard workers who can run into a bad outcome, but this should happen only very occasionally, and if they have any cases listed the list should be very short. Some of the doctors who take care of the most complicated cases are more likely to be sued. That being said your hospital or insurance company should evaulate each case and avoid the frequent fliers.

And then there’s the internet. Have you ever stayed at a nice hotel and enjoyed the experience? Go to the internet and check the reviews, you would be surprised by all the negative comments. But, the average of the reviews would at least be close. So yes, the internet chats are some of the best places to find doctors, especially if you repeatedly read similar concrete reasons why a doctor is good or bad. I have heard of administrators going undercover on the sites to steer business to their doctor, so watch for that.

More on the best doctor for you next time,

Dr. Licciardi

Your Doctor’s IVF Pregnancy Rates are Available to You

The majority of reputable IVF clinics are members of an organization called SART. This stands for the Society of Assisted Reproduction. Almost all members SART submit their pregnancy rates, via computer, to the SART office. SART then works with the Center for Disease Control (otherwise known as the CDC) and produces a report. This report has the pregnancy rates for each clinic in the country. It can be viewed by going here:
http://www.sart.org/
Just click on the state and look for your clinic.
The charts are a little confusing. Pregnancies mean just that, so some pregnancies end in miscarriage. You want to look at the live births per retrieval. This means the chance of having a baby if you made it to the point where your eggs were removed. Once you see this clearly, it’s easy to click onto any clinic’s page and look at their rates for comparison. If your clinic is not listed, that’s a very bad sign. Some are not listed because they are too new to get on, but most who don’t report don’t report for a reason: their numbers are low. There is no excuse for a clinic not to report. Some will say they don’t report to SART because SART does not calculate the numbers correctly: not so.
You can also see that there is a delay in reporting. This is because deliveries occur well after the IVF cycle, plus it takes some time to get the reports out. This gap will decrease as SART improves its computer technology.
If your doctor doesn’t report, beware. If your doctor blurts out numbers (this is really common), the numbers are usually exadurated. Go to the web and check the facts yourself. And don’t listen to anyone who says their numbers are lower because they take the harder cases. The clinics with the best numbers have the best reputations and attract many many women who have failed other clinics first.

Pregnancy Rates Matter

You have choices. Many of you live in areas where there is more than one IVF center. Choosing a center is one of the most important decisions you will make. How do you choose? Well, most of us get a referral from a friend or doctor, and then go and check it out. If we like the doctor we saw, we assume he or she is the very best, and go with the recommended treatment plan. Well, there are a lot of clinics that are very popular, get many local referrals and have very nice doctors and staff. The problem is that many of these clinics have low pregnancy rates, and they are not advertising this fact. Why does it matter? Compare a good clinic with a pregnancy rate of 50% to a not so good clinic with a 30% pregnancy rate. The math is easy: out of 100 patients, 50 had a baby on their first try at clinic 1, while only 30 had a baby at clinic 2.
Don’t ever listen to a doctor or nurse who gives you pregnancy rates that are not in writing. Next post I will tell you the real way to get pregnancy rates from each clinic.

What are Your Odds?

I bet that most of you don’t know. You were never told, but you should have been. I’ll go through it now. Please understand that many of the numbers are estimates.
Let’s start with trying on your own. In the first try, if you are under about 35, it is about 30%. In the second month it goes down a little, and if you are not getting pregnant, it goes lower and lower each month. In your 13th month (after about a year of trying), it’s 3%. The reason it gets lower is that if you are not getting pregnant, there is probably a reason, and your odds were really 3% in your first month. The numbers are a little higher if you’ve had a baby. They are lower if you are older. Many people are surprised by this number, but it’s been studied again and again. The goal of fertility treatment is to increase the 3%.
Clomid with insemination is 8%, lower if you are older. FSH IUI is 20%, but only 5% in women over 40. Future writings will discuss these drugs separately. Subtract a few points without the IUI. Subtract points for low sperm counts.
To help answer the question about when to go to IVF, just look at the numbers and decide. Cost is another factor to consider. On one hand, Clomid IUI is a lot cheaper than IVF, but on the other, the cost of 3 cycles of monitored Clomid IUI can add up. Many women with a normal HSG and good sperm do a few cycles of Clomid IUI, then a few cycles of FSH IUI, then IVF. However, there are no rules about this. After hearing the odds, especially when accounting for age, some quickly go to IVF. I’ll discuss IVF pregnancy rates later.

References:

  • Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, Hill JA, Mastroianni L, Buster JE, Nakajima ST, Vogel DL, Canfield RE. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. N Engl J Med 1999; 340(3):177-83.
  • Dankert T, Kremer JA, Cohlen BJ, Hamilton CJ, Jong PC, Straatman H, Dop PA. A randomized clinical trial of clomiphene citrate versus low dose recombinant FSH for ovarian hyperstimulation in intrauterine insemination cycles for unexplained and male subfertility. Hum Reprod 2007; 22(3):792-7
  • Boomsma CM, Heineman MJ, Cohlen BJ, Farquhar C. Semen preparation techniques for intrauterine insemination. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD004507.