Canadian IVF Cycle Fails: Husband Asks, Try Again?

Question:

Hello Dr. Ramirez and thank you so much for answering these questions.

My wife and I just completed our first IVF (although there was no transfer).  A previous attempt was cancelled due to only a couple follicles (150 Gonal F/150 Menopur).  We had done 2 previous IUIs with Clomid (3 follicles).

My wife is 37 and has very low AMH (0.40), FSH that ranges from 7 to 14 and an AFC of 6 to 14.  My analysis has been normal but we were recommended ICSI as it was unlikely we would get many follicles.  The clinic said they generally like to aim for 2 good ones.

To bring down FSH, my wife used an estrogen patch before her period and had 3 Ganirelix injections.  She then started 300 Gonal F & 150 Menopur on Cycle Day 2.  From Day 9 to 15 she also used Ganirelix. She was told to change the patch every other day and on cycle day 4 stop changing the patch (but it would last 7 days so would still have medication until cycle day 10).

She was slow to respond, not developing any measurable follicles (greater than 1.0) until after 7 nights of stims, but in the end, used the same Gonal/Menopur dosages for 15 nights.  Her AFC had been 14 and when she triggered (with 10,000IU HCG) on night 15 she had 7 follicles (2.2, 3 at 2.0, 1.6, 1.4, 1.0).  On trigger night her e2 was just over 2,500 (I have converted this to the U.S. value - pg/nl). 
 
35 1/2 hours later was retrieval.  They got 4 eggs and had to skip a few on one ovary due to blood vessels. The next day the embryologist called and said they had been able to ICSI 3 of the 4 and as of that morning (day after retrieval) only 1 of the 3 remained.  The next morning (2 days after retrieval) they called to say that embryo failed to divide.  It was the same the next day so there was no transfer.  They didn't have a definite answer as to why but said one of the eggs was soft and they weren't all smooth so it is probably egg quality issues.

Also - up until day 11 of stims her lining had been building well daily (to 1.2 cm).  Over the next 3 consecutive days it got thinner each day (even though e2 was rising) and was 0.9 the day of trigger.  Her lining has never been a problem in any other cycle (natural or medicated - even on Clomid).

We are trying to decide if it is worth it to do another cycle.  Could this be a fluke?  Could the long stim period have compromised egg quality (in addition to her age/FSH/AMH?)  Could ICSI have damaged the eggs at all if they were soft?  Will the blood vessels mean some follicles have to be left in one ovary at every retrieval?

Did the thinning lining indicate anything - coincidentally - when the lining started thinning her own e2 was raising daily quite a bit, but this was the same time the medication from her final estrogen patch would have worn off.  She had a bit of bleeding a few hours before the trigger shot on night 15 and was put on 8 mg/day of estrace the day of retrieval in addition to progesterone because of that. 

I would appreciate your advice.  We would like to try again but I don't want my wife to have to go through another cycle of injections/monitoring/retrieval, etc. if our results would be the same.  She had 12 days of blood tests & ultrasounds between day 2 & 15 and the 12 blood tests made it really hard to find a vein for IV at retrieval which took a couple tries.

We would like to at least make it to transfer before considering other options, but if we can't develop embryos in a lab, we're not sure if we should try again.

Thank you,

T. from Ontario, Canada

Answer:

Hello T.  from Canada,

A lot of the answers you seek are due to technical quality issues and I cannot address that.  Without a thorough review and evaluation of your wife's medical records, I cannot evaluate if I would have done things the same or differently, and whether or not that will make a difference.  Suffice it to say that I am saddened by your results, but at the same time, I am a little leery about some of the embryology outcomes.

Let me just give some information that might help you in your review. 

1.  The dosage of 350/150 is NOT the highest stimulation protocol.  Your wife could go up to the max dosage of 450/150 which might make a difference in the number of follicles recruited. 

2.  Based on the number of follicles formed, she actually stimulated well so the AFC, AMH and FSH may not be valid in predicting her decreased ovarian reserve (which does not predict fertility).

3.  I have not heard of the failure to retrieve due to "veins" or "blood vessels".  There are techniques that can be used to move and manipulate the ovaries to avoid those problems.  I have, however, had patients where I could not retrieve completely because the ovaries moved too much and deep into the pelvis.

4.  I think that ICSI in a 37 year old woman is appropriate and would concur with doing that procedure.  Keep in mind that ICSI is a procedure and "technique and skill" are critical to preventing damage/injury to the embryo.  It has been shown that ICSI done by an embryologist without adequate experience and skill can reduce embryo survival.  That could possibly have been a problem, but certainly inherent egg quality can influence that as well.

5.  Embryo quality (based on external features) are certainly based on inherent egg quality and that decreases with age.  However, that does not mean that all the eggs are bad.  Studies have shown that at 37 years old, 2 of 10 embryos formed will be normal.  The trick is to find the two good ones.  That may take several attempts or you would have the option of moving to donor eggs.  Since you have never completed an IVF cycle, you certainly have not tested whether or not it will work.

6.  Finally, I don't think I have ever had a patient that needed 12 blood tests during an IVF cycle.  The maximum I've had was 7.  Keep in mind that IVF success rates are highly variable between clinics and doctors.  Even in the U.S., rates are highly variable as compiled by the CDC.  I'm sure they vary greatly in Canada as well.  Based on what you have told me in your review, I can't help but be a little skeptical of the level of care you are receiving, but again, I can't draw any conclusions without a careful review of your records.

Good Luck,

Dr. Edward J. Ramirez, M.D. F.A.C.O.G.
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Programwww.montereybayivf.com

Comment: Thank you very much for your quick and helpful response.

 

A Step By Step Guide To The IVF Process: Step Six -- Embryo Development

Blastocyst
 

Dear Readers: This is the sixth part in the series I have begun to help answer what In Vitro Fertilization (IVF) is and how it works with my world-wide Blog audience. What you read here is what I also provide my patients with on a daily basis. I plan on going into some detail but in a way that is understandable to the normal (lay) audience, and not the medical or scientific one. I also hope that this will not only clarify what you will go through, but explain why things are done a certain way and what the goals of each step are. I also want to convey that IVF is actually a replacement for some of the “natural” steps required to get pregnant and not some miraculous high tech fertility treatment that gets patients pregnant artificially, as many think it is. It is somewhat of a miracle that we can do as much as we can, but there are still lots of things/steps that we cannot do or influence. I hope this discussion will benefit you. This series will continue to be posted over the next few weeks in installments. (For earlier installments in correct order scroll down to the beginning of July 2012.)

STEP SIX: EMBRYO DEVELOPMENT

At this point, we have gotten the eggs out of the ovaries, put them with the sperm or injected the sperm into them and fertilization has occurred. Each of these steps has lead to a decrease in numbers from the original number of follicles. Not all the follicles had eggs retrieved from them, not all of the retrieved eggs were mature and therefore could not be fertilized, and not all of the mature eggs fertilized or fertilized normally. So now we are left with a cohort of embryos that have fertilized normally and are ready to grow and develop into embryos that can be transferred.

At the end of fertilization, normal embryos are in a 2PN stage, or two pronuclei and is one cell. These are placed into special media that provides the proper nutrition for these early embryos to grow and develop. This is key for the growth of embryos. Embryo culture media has been researched and developed over the evolution of IVF technology, researching and finding the proper combination of chemicals to mimic the intratubal environment. In the natural process, the embryo is within the tube and develops and divides as it makes its way down toward the uterine cavity. So the culture media has to match the media that would be found within the tube. In addition, the environment, such as gas ratios and temperatures, have to match as well. So the requirement for embryo development is to have the proper nutrition within the Petri dish, the proper temperature within the incubator and the proper gas mixture within the incubator as well. Also, the embryo needs to be protected from airborne contaminants outside of the incubator. These factors are so critical that they will influence the success rates of an IVF clinic.

Many embryology labs, such as mine, are designed and constructed to the standards of a “clean” room, such as that used in Silicon Valley for making silicon chips. The airflow within the room is isolated. In other words, the airflow is completely separated from the air outside of the room so that there is little contamination from in the outside. In my lab, the airflow is set to be a positive flow, meaning the air pressure within the room exceeds the pressure outside the room so that when the door is opened the air pushes out rather than allow the outside air to push into the lab. In addition, the airflow within the lab is cleaned by a HEPA filter and Charcoal filter to filter out small particles and chemicals, called VOC’s or volatile organic compounds. VOC’s are the fumes or gasses you can smell after a room is painted or a road is repaved, but there are VOCS’s that can’t be smelled as well. These chemicals can kill or injure embryos so that they don’t continue their development. Finally, the embryology lab temperature must be maintained so that when the embryos are taken out of their warm environment to be checked, their temperature does not drop abruptly. When choosing an IVF clinic, it would be wise to ask about their lab set up and, if possible, tour the lab to see how well the environment is. Many centers have certification by the College of American Pathologists (CAP) which means they have undergone a survey, which includes evaluation for many of the aforementioned criteria for labs, and have passed and received certification of their lab.

If all of the above quality controls are in place the embryo can proceed with development to a stage where they can be transferred into the uterus. The embryo actually can be transferred at any point in its development, but time and research has identified the two optimal embryonic ages as day #3 or day #5. These are the two ages that most IVF centers in the world use in their transfer protocols.

So, by the day after fertilization (48hrs after retrieval) has taken place, the embryo has developed into a 2-4 cell embryo, in normal development. Sometimes embryos will have progressed further than 4 cells but that can either be because the evaluation of the embryo was later in the day (48hrs) or the embryo is developing faster than expected, which could be an indication of an abnormal embryo. Embryos are also examined for external features and a grade is given. There is no universally accepted standardized method for grading but they are all essentially similar. They are all based on the external or “morphological” characteristics of the embryo as viewed through a microscope. Almost all labs will count the number of cells that the embryo has on that particular date, up to the Morula stage where individual cells are no longer visible. They will also give it a grade (A,B,C or 1,2,3) based on the clarity of the embryo. That is, the amount of fragmentation or debris located within the cell. These fragments are pieces of tissue that have been extruded in cell division. Although cells with high amounts of fragmentation have been related to decreases in pregnancy rates, that is not an absolute. I have had the worst looking embryos lead to pregnancy, as have many other clinics. But, we know that most successes come from cells that either don’t have any fragmentation or a minimal amount. Finally, most clinics will look at the symmetry of the cells; do they look fairly equal or are there larger and smaller cells. In my practice, we use a simple 1,2,3 grading system where the embryos are evaluated for fragmentation and symmetry, and the combination of those two factors lead to a grade. Some clinics break these down and give two grades for each embryo; one to represent fragmentation and one to represent symmetry, and some use letters instead of numbers. In 2010, the Society for Assisted Reproductive Technologies released guidelines for grading embryos in the hope of standardizing this among IVF centers within the United States. In their system, cleaved embryos (those before morula stage) are evaluated for the number of cells present, fragmentation (0%, 1-10%, 11-25%, >25%) and cell symmetry (perfect, moderate asymmetry and severe asymmetry). Embryos are then given a score of Good, Fair or Poor.

The biggest disadvantage of current embryo evaluation methods is that it is essentially a beauty contest, so as I explain to my patients, Grade A or 1 or Good is “beautiful”, Grade B or 2 or Fair is “average” and Grade C or 3 or Poor is “ugly.” We know that most pregnancies come from Grade 1 or 2 embryos and only Grade 3 embryos have a decrease in pregnancy rates. This method does little to evaluate the internal quality of the embryos, which we know is really the main determining factor for embryo health or viability. That technology is yet to be developed. Embryo chromosomes can be determined by removing one of the cells and checking for its chromosomes, a procedure known as Preimplantation Genetic Screening (PGS/PGD), but this still does not evaluate the structures within the cytoplasm, or outside of the nucleus where the chromosomes lie, which are the structures that provide the energy for the embryonic cell. When looking at embryos to decide which to transfer, not only must the embryo appearance be taken into consideration, but its development rate must be considered as well, as an indirect measurement of embryo health. I’ll discuss this decision more in the next step.

To summarize the stages of development, at 24 hrs after egg and sperm have been put together (day of retrieval), the embryo is a 1 cell 2PN; at 48 hrs (Day#2) it is 2-4 cells; at 72 hrs (Day#3) it is 6-8 cells; at 96 hrs (Day#4) it is usually a compacting Morula; at 120hrs (Day#5) it is a Blastocyst. There is some variability to this development scheme as embryos do have differences in rate of division. In a natural (non-IVF) cycle, the embryo is usually at the Blastocyst stage when it reaches the endometrial cavity. In IVF the transfer is done either on Day#3 or Day#5. Because of the political pressure to do more single embryo transfer cycles, or 1 embryo transfers, many clinics are now culturing to Blastocyst stage before doing the transfer. This is because culturing to Blastocyst stage leaves less embryos to choose from and MAY indicate a healthier embryo, but the latter conclusion is not an absolute.

In my center, I have specific criteria to determine whether or not to proceed to Blastocyst. One of these criteria is that there has to be a minimum of 8 good quality embryos (7-8 cell, grade 1) because I know that many embryos will not make it to Blastocyst, and that is not necessarily because the embryos are bad. In doing PGS, I have seen Blastocysts turn out to be chromosomally abnormal embryos whereas an embryo that did not survive to Blastocyst had normal chromosomes (PGS usually is done with Day#3 embryos and takes two days to get the result so by the time the result comes back, the embryos are Day#5). I have also seen ugly poor looking embryos (4 cell, Grade 3) lead to pregnancies when transferred at Day#3 that would not have survived to Blastocyst. My reasoning is that Blastocyst culturing is not a perfected technology yet. A clinic that puts only a few embryos at risk to develop to Blastocyst is basically risking the cycle by not having anything to transfer. For that reason, I want to make sure that there are enough embryos to start with so that there will be embryos to transfer. In addition, it is still my personal belief that the uterine cavity is a better culture environment and media than what we have available in the lab. For this reason, most of my transfers are on Day#3, but I have colleagues who now transfer mainly Blastocysts. So, when looking at these transfer options with your doctor, ultimately the decision has to be made based on pregnancy rates at Day#3 vs Day#5 transfers and not just because you only want to transfer 1 embryo.

In the next entry we’ll discuss embryo transfer and the decisions that go into this step, as well as, the critical parts of the transfer technique.We will continue this discussion soon with the next installment, "Step Seven: Embryo Transfer". Thank you for joining me today!

Edward J. Ramirez, M.D. F.A.C.O.G.
Medical Director, Monterey Bay IVF
Monterey, CA
http://www.montereybayivf.com/

First IVF For Indian Woman Results In Implantation Failure: Perhaps Nothing Can Be Done But To Try Again

Question:

Hi Doc,
I am 28 yrs old and underwent my 1st IVF cycle this month. My infertility diagnosis was endometrioma on right ovary , the cyst was removed by laparoscopy 1.5 years back. Twelve eggs were retrieved in total from all 12 follicles that formed.

The IVF cycle yielded good quality embryos and ET was done on day 2 of egg retrieval. In which 4 embryos were put, 3 of grade A and 1 of grade B.

Post ET medicines included progesterone/estrogen support and aspirin along with Dexamethosone. Even after every thing being perfect till end my b-HCG test resulted in level if 1.50 miu and after 48 hrs it was 1.69 miu. Please suggest, according to u what could be the reason for the implantation failure even when everything seemed good.

I'm writing in from India. Thanks and regards, R.

Answer:

Hello R. from India,

IVF is not a perfect technology and does not yield a 100% pregnancy rate. This is because the last two steps in the process to achieve pregnancy, embryo hatching and implantation, are things we do not have the technology to make happen. So, there is a little "chance" or "luck" with IVF. Certainly there are other possible causes of failure, such as embryo transfer technique, embryology laboratory quality, timing, endometrial thickness, immune factors, etc., but with the information that you have given me, I cannot determine if any of these might be the case. I too have young women who have perfect appearing embryos and great transfers who do not get pregnant. It stumps me, but then I remind myself that I am not dealing with a perfect technology, despite doing the absolute best that I can do (and I am pretty good at this treatment), and that GOD reserves the right for himself to produce life and determine when it happens, not me.

For you, you need to just keep trying. It will eventually happen, and usually occurs by the third attempt. Keep in mind that even a "normal" woman your age, trying for natural pregnancy does not get pregnant on her first try. The average number of times that it takes a woman under 30 to achieve natural pregnancy is 8 months (8 tries).

Final note: Please refer to my July 2009 blog post on IVF Implantation Failure: womenshealthandfertility.blogspot.com/2009/07/ivf-implantation-failure.html for further information. You may want to glance at the comment section as well, as there are many questions from readers which I have answered with more details regarding this disappointing aspect of IVF.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

Secondary Infertility, High Responder PCO Patient: Why Did I Fail Two IVF Cycles?

Question:

Hi, I am 28 years old and my husband and I have a naturally conceived 3 year old son. We are dealing with secondary infertility. We have gone through 2 IVF cycles.

1st IVF/ICSI cycle-21 eggs--11 fertilized (70% fert. rate)--transferred 2 great 8 cell embryos. None to freeze. Negative result

2nd IVF/ICSI cycle

19 eggs--(85% fert. rate)--8 embryos on day 3

1-8 cell grade 1 (best)

2-8 cell grade

21-8 cell grade

32-7 cell grade

22-5 cell grade 2

No transfer because of lining issues. Did one FET--ended in a chemical pregnancy.

My question--do I have poor egg quality? Lab results said some eggs were abnormal, with thicker zona. Any hope to go through IVF again?

I'm from Fargo, ND. Thanks in advance!

Answer:

Hello M. from North Dakota,

From the number of eggs retrieved, I presume you also had a high number of follicles (>20). That indicates that you are responding like a PCO patient, or have PCOD. Studies have shown that there is a decrease in pregnancy rates with PCO patients, probably due to a high number of immature eggs retrieved. It also seems to affect egg quality. That is not because you have abnormal eggs, it is probably because the PCO causes an inefficiency in egg maturation.I would not give up hope. In fact, I would encourage you to continue trying because you will be successful. It may take some more tries, and hopefully, your doctor will adjust your protocol to try to reduce your stimulation. It would be better to have fewer follicles with good eggs than lots of follicles with poor eggs.

By the way, I just had a patient from your end of the country, Montana, that previously went to a clinic in Washington state and had two failed IVF cycles. She was a secondary infertility patient as well. Well, the change in weather or location or clinic did the trick because she became pregnant with one attempt, and with twins. Infertility Physicians and clinics are not all equal. That may have a bearing on your success as well. I am worried about the fact that despite all the eggs, your embryo quality rate and number to freeze were so low. That might also indicate a laboratory issue.

In any case, don't give up hope. You will eventually be successful.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

Comment: Thank you for your insight! Very much appreciated! :)