High Responder Fails Two IVM and Two IVF Cycles: PCOD & Follicle Maturation Issues

QUESTION: Hello,

During the last year we did two IVM (in vitro maturation) and two IVF (in vitro fertilization) cycles at different clinics at Montreal, Canada. All failed. I'm 39 years old and my husband is 40. My FSH was 11.1 and AMH 2.2 two years ago. The first IVM was without stimulation, I was triggered when the lead follicle was 13mm, 11 eggs were collected, 7 managed to mature in the lab and 4 fertilized. By the day 3 we had transferred 2 embryos 6 and 8 cells (they did not give us their grade). Endometrium was 6.8mm by the day of collection. No pregnancy...

The second IVM I had 3 days light stimulation (about 150UI Puregon days 3-5 + Estrace from day 6). I was not aware of my hormone test that shown the E2 level fell on day 6. We had collected only 8 immature eggs from 17 follicles, the only egg fertilized and on the second day the weak embryo was transferred. Endometrium was 7.3mm. Of cause, no pregnancy.

We moved to another clinic and did there two IVFs. The first one I had stimulation from the second day: 225 Gonal-F + 75 Luveris. After 4 days dosage was increased up to 300 Gonal-F + 150 Luveris. On the day 13 I was triggered when I had one follicle about 22mm, 2 about 18mm, and many smaller ones. We collected 16 eggs, 12 were mature, 9 fertilized. My doctor decided to wait till day 5 for the transfer. We had one blast, the other embryos stopped developing. The lining was 8.2mm at the day of transfer. No pregnancy.

As the clinic doesn't work during weekends, the stimulation for our second IVF started on day 4 and lasted 9 days. It was more aggressive: 300 Gonal-F + 150 Luveris from the start and about 200 Gonal-F + 150 Luveris at the end as I had developed mild OHSS. I was triggered when my follicles were 1-19mm, 1-18mm, 3-16mm, and many 15mm and less. As I said the clinic doesn't work weekends. My collection was Friday. I asked to wait for follicle growing bigger and the answer was: no, they are big enough. We collected 25 eggs, only 13 were mature, and only 5 fertilized. They were stopping developing one after another. The last one stopped at day 6 on the morulae stage. The lining was perfect: 13.5mm. It was an epic failure: nothing to transfer... I was told that the issue is my egg quality (my husband has no issues with his sperm).

I see that I had the only follicle bigger 20mm at the collection and we had the only blast. So I really would like to understand whether it's not a coincidence? If there is a way to have more equal size of follicles by changing the protocol? If I'm a good responder and have many eggs and they usually fertilize good (if they are mature) but they stop developing - does it mean they are poor quality? Or they were not fully mature at the day of collection? As I'm getting older and we have no time to experiment with different protocols I would like to maximize our chances by using more effective protocol for our next attempt. It would be great to hear your opinion on it. Could the change in protocol give us better chance for success?

Thank you in advance! O. from Canada.

ANSWER: Hello O. from Canada,

I can't give you specific protocol recommendations because each doctor and each clinic do different things. There is no one way to do IVF as you have found out.

The latter stimulation cycles show that you are NOT a poor responder but a high responder with PCOD tendencies. That means your ovaries are very sensitive to stimulation and that is a good thing. Yes, your age and therefore your egg quality are issues. However, hope is not lost because there is a chance that you still have a few good eggs left. As long as your ovaries respond well to stimulation, your chances of finding the good eggs are high. However, it also means that you need to find the right clinic because pregnancy rates will vary highly depending on the skill of the clinic and factors such as when to retrieve. I think it is a mistake to go to a clinic that only does egg maturation, and a clinic that doesn't work weekends. Both clinics are short changing you. It's time to find a better clinic.

It is also known that when OHSS develops, the pregnancy rates also drops. Probably because the majority of the eggs are not adequately matured. So one goal would be to decrease the stimulation and try for fewer eggs and a longer stimulation to get higher quality eggs. That is my goal with patients that are high responders. One method I use to try to even out the stimulation is to use the "sandwich protocol" which is to use 2-3 days of antagonist prior to starting the stimulation (I don't use the long Lupron protocol)to suppress the ovaries so that the follicles all start at the same point. Not all doctors use this protcol.

One final note: I let my follicles reach 20 mms before trigger. In some cases, I'll go up to 24 mms on the lead follicles if there is some unevenness, the goal of which is to try to get as many mature eggs as possible. Again, these things/variations are what make clinics and doctors different. You need to find a clinic that has a respectable pregnancy rate for your age group (and that will stay open on the weekends) so that you don't waste any more IVF cycles.

FOLLOW-UP QUESTION:

Dr. Ramirez,

At first, thank you very much for your fast and detailed response.

I've forgot to mention that our infertility is unexplained and I always have a lot of follicles at any given cycle (the first time we asked medical help for infertility 4 years ago).

Today I've got some new details about my IVFs: first time the E2 was about 8000 at the day of trigger and progesterone was about 4. The second time E2 was more than 22000 and progesterone was 6.4 so that my doctor didn't wait anymore and triggered me when the lead follicle was still 19mm (and not because they do not work weekends, as he explained). Is it possible that the E2 level could compromise egg quality the second time?

My doctor told me that assisted hatching is not possible for a blast as it can be easily damaged. Do you agree with that? Is assisted hatching used for day 3 embryos only?

Also my doctor is tended to wait for a blast and do 5-day transfer as he believes it would give stronger embryo and higher chances of implantation. As I see we had many good-looking embryos on day 3 and 1 or no blast at day 5. Would it better to transfer at day 3 instead?

Thanks again for sharing your knowledge

Regards, O. from Canada.

FOLLOW-UP ANSWER:

Hello again,

You have to understand that my advice is my personal opinion and not necessarily the gold standard or generally accepted standard because there are many many variations in the stimulation portion of the IVF cycle. But let me give you my opinion.

Both cycles led to overstimulated cycles. If the peak E2's are correct, you went very very high and in the U.S., in general, we don't like the E2 to go above 4000. Yes, it has been shown that when hyperstimulation occurs, i.e. the E2 goes above 4000, there seems to be a decline in egg quality and pregnancy rates.

You don't necessarily have a diagnosis of "unknown" infertility. You have the "age factor" which means that your egg quality could be compromised based on your age. That is a diagnosis. My approach to transfer is to use D#3 transfers unless I have so many good D#3 embryos that it is harder to determine which ones to transfer. In that case I will proceed to D#5. I am not a big D#5 person because I don't think that it is an absolutely perfect technology and we probably lose some good embryos because of it (that has been shown by genetic testing of the embryos on D#3). Not all blastocysts are genetically good embryos. Because of your age, I don't think it makes any difference which day you transfer, but I would prefer to put back more and let nature decide that the lab. YES, assisted hatching can be done on blastocysts.

The only other option that might help you, is to consider preimplantation genetic screening so that only normal embryos are replaced. I would also recommend tranferring at least 4 embryos because of your age. PGS might decrease your pregnancy chances a little, depending on the expertise of the clinic, but can help you to distinguish the genetically normal from the abnormal. PGS can be done on D#3 or D#5.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com

Comment: Dr. Ramirez gives detailed and clear answers. He is extremely helpful and very knowledgeable.

40 Year Old UK Woman Trying IVF After Implantation Failures: Assisted Hatching & PGD?

PGD

QUESTION:
dear doctor ramirez, i am so glad to find you on this website and would very much appreciate your help. I will try to give you some background.

i have had 3 failed iui, then found problems with my fallopian tubes which led to bilateral salpingectomy, myomectomy, adhesiolysis and cornual tubal occlusion, left ovarian cystectomy, i also have fitz hugh curtis syndrome.


so then after recovery from the above op i had

one fresh ivf cycle - 18 follicles, 14 eggs collected, 8 fertilised, 3 day transfer of 2 embryos(8 cell, grade 2)on 18/10, started bleeding 30/10

fet - 19/3. 2 embryos transferred (5 cell grade 2 & 7 cell

grade 1-) Negative test 4/4

fet - 9/8. 2 embryos transfered (6 cell grade 3/3 & 3 cell grade 4/4) Negative test 24/8

on each occassion as you can see i had 2 embryos put back (blastacysts on the last fet) and all failed at implantation stage. these were in 2006 & 2007.

now in june 2012 i have started my ivf journey again. so far:

low amh result (i am 40 in october)

2 new fibroids found on ultrasound, advised to proceed anyway

down regulation extended 1 week as lining not thin enough

stim injections all went to plan

15 follicles (2 v large suspected to be cysts)

10 eggs retreived

7 fertilised

7 made it to blast but one left to perish as structure wasnt great.

2 fantastic blasts put back after using embryoscope which i was told had started collapsing which was explained as a very good development.

4 frozen.

so, 2 put back in and progesterone pessaries used one morning & 1 night.

day 5 post transfer sign of period.

evening of day 6 post transfer period definately started with heavy bleeding & clots, continued until today (day 9pt) flow seems to be slowing down.

negative test today 9dpt

clinic advised me to continue with pessaries and re-test on saturday (day 11 pt)
theres the background for you, so here are my questions:

1. why am i failing at implantation stage every time?

doctor says it just nature but i cannot help feeling something else could be wrong and i am running out of time

2. is there any kind of contraception or other medication that i could use to stop producing eggs, thus preserving the small reserve i have left?

3. what tests can i have done to rule out ANY other problems? ie immunology, uterine probs, endometrium probs?

4. fibroids-what should i do have them removed or is there any medication available that may shrink them before my next fet

5. assisted hatching-could this help?

6. pgd (preimplatation genetic diagnosis)?

7. having read my history but you advise i do????

if need be i will pay for any tests that they wont complete at my clinic. i feel if i can rule all other possible problems out then i can admit that yes it is in gods hands and just a matter of keep trying but at the moment i feel what if there is something else that is being overlooked?

many thanks for your help in advance doctor.

as you can see i am getting pretty desperate now!

lisa, uk

ANSWER:

Hello Lisa from the U.K.,

The term "Implantation failure" means that the last two steps of the reproductive process did not occur. These last two steps are natural steps and we do not have the technology to make them happen. That is why IVF is not a perfect technology. Once the embryo is placed into the uterus, the embryo has to hatch out of its shell and attach to the endometrial ining. Then the endometrial has to engulf the embryo (implantation). So either of these two steps could have been the source of failure. In addition, it is well know that pregnancy rates will vary from doctor to doctor and clinic to clinic because the transfer technique can play a significant role.

In your previous cycles, your embryo quality was poor. I am not surprised that they failed. In this last cycle, despite having good blastocysts, there is still a potential deficiency that they have. This is because of your age, or what I refer to as the "age related egg factor." We know that as the eggs age, the internal structures of the egg become more debilitated and so less likely to thrive. One of these deficits is the chromosomal structures are more brittle and can lead to chromosomal abnormalities as the cell is dividing. Without doing genetic testing, these cannot be detected. Even chromosomally abnormal embryos can turn into good looking embryos but not necessarily into pregnancies. That is another possible source of failure. IVF helps to overcome this problem by increasing the number of eggs retrieved and therefore, statistically, increases the chances of finding the perfect egg. But that does not occur every time. You will have to keep trying in the hopes of finding the perfect egg eventually. The good thing is that your ovaries are still very responsive (you don't have decreased ovarian reserve and stimulate well), which gives you a good chance.

In terms of your other questions, I would not do anything with the fibroids, any birth control pill can stop your ovaries from going through the ovulatory cycles and hopefully preserve your eggs and I can't think of any other testing. Without thoroughly reviewing your medical record, however, it is difficult for me to give you specific advice.

I would recommend assisted hatching as this has been shown to increase pregnancy rates in older patients. I would also recommend that you scrutinize your clinic, because of all the failures. Pregnancy rates can be very clinic and doctor dependent. You should try to find one that has good pregnancy rates for your age group. I am getting a 57% pregnancy rate in 40 year olds and many of the clinics in the U.S. are getting similar results. I would also recommend that you consider transferring more than two embryos (we allow up to 4 in 40 year olds).

You faith in God will help you through this, and eventually it will happen. You may have to change course at some point and look at a different approach, but your faith will get you to that dream of having a child. When I complete my embryo transfers, I say a prayer with each of my patients and ask God to bless my couple with fruit of the womb and grant their wish for a child. I am confident that he will do so as He wills it.

Good Luck

FOLLOW-UP QUESTION:
hi doctor

thank you so very much for your speedy and detailed response, it has set my mind at rest on a lot of points. it is interesting to be told that the quality of the embryos on our cycle a few years ago were of poor quality. although that is sad, at least now i can accept that maybe that is why we failed on those 3 occassions. i had been under the impression that the embryos were good quality, particularly on the first fresh cycle after egg collection.

i have read lots on assisted hatching and am glad you agree this may be a way forward for us.

can i please just take a few more minutes of your time to clarify my point on pgd & other test (point 3&6)

When you mention checking the quality of the eggs/embryos were you suggesting asking our clinic to go ahead with pgd for our next fet?

also what is your opinion on other testing such as Natural Killer cells, immunology, uterine/endo probs? Which of these or any other tests would you suggest i rule out before going ahead with our fet?

also you mention my ovarian reserve being good but i was under the impression that the AMH test i had done suggested i was on the bottom level in terms of my remaining eggs? this has confused me slightly?

thank you in advance.

many many many thanks for you time again. Lisa

FOLLOW-UP ANSWER:

Hello Again,

There are pros and cons about using PGS. It can help to identify embryos that are chromosomally abnormal so that you can be more selective in the ones that you transfer. The downside is that there is a decrease in pregnancy rates, probably because of the impact of the biopsy on the embryo.

I check certain immunologic testing on my patients that fail two or more IVF cycles. The tests I choose do not include natural killer cells because I don't believe in that concept as a source of implantation failure. Despite this testing, I also automatically place my patients on low dose aspirin, low dose heparin and medrol, as well as, increase the progesterone supplementation. The latter is the treatment for patients that have endometrial biopsy for beta integrins and find that they are deficient. I figure, why waste money on doing the test and just cover any ways, since increasing the progesterone is the treatment.

Remember that AMH is an "indirect" test for ovarian reserve and does not necessarily predict how you will respond. Your have already shown good response so it is not an issue.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.

Smoking And Infertility

Question:

Dear Dr. Ramirez,

I'm 18 and I just started smoking, but I'm afraid it will effect my ability to have children. I know smoking can cause cancers, but in females, does smoking cause permanent infertility? A friend of mine told me it just causes temporary infertility, and since I'm 18 and no where near ready for a baby, I wasn't too worried. But I do want to have children when I'm older. Could you please help give me advice on this? A. from Georgia

Answer:

Hello A. from the U.S. (Georgia),

Smoking does not cause permanent infertility but has been shown to affect fertility i.e. reduce the chances. More importantly, it can cause other permanent diseases such as lung cancer, heart disease, throat cancer, stroke and deep venous thrombosis. Smoking at the time of pregnancy can lead to poor fetal development, poor fetal outcomes and other complications.

Because smoking reduces the blood vessel diameter (vascularity), it affects the chances of pregnancy by reducing blood flow to the implantation site, developing embryo and placental flow. There is also an increased risk of miscarriage.

I hope that gives you enough reason to stop while it is still easy to do so. Keep in mind that smoking is a ADDICTION and gets harder and harder to stop with time.

Good Luck,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com