Tuesday, February 7, 2012

Third Failed IVF Cycle: New Protocol Needed? Compare SART Stats?


Dr. Ramirez,

I just had my 3rd failed IVF cycle and I'm looking for some guidance. A little history:

I am 31 have a short luteal phase but PIO and estrace seem to do the trick. Day 3 testing normal. My husband has low morphology.

My 1st IVF attempt I responded very well (long lupron) to low doses of meds. Stimmed for 7 days. They obtained 10 eggs and 9 fertilized with ICSI... all were very good quality on Day 3. Transfered 1 and 5 frozen on Day 3.

2nd IVF attempt- Antagonist Protocol- very slow to respond on highest doses of meds. Didnt have any measureable follicles until Day 10... stimmed for 15 days. Obtained 6 eggs and only 3 fertilized with ICSI. Transfered 2 embryos on day 3. Negative beta 10dp3dt and stopped meds. Discovered 2 weeks later that I was pregnant and miscarried.

3rd IVF attempt- back to Long Lupron- very slow to respond again on highest doses. Stimmed for 15 days- obtained 8 eggs- 4 fertilized and only 2 were viable on Day 3. Beta negative.

Questions:Any thoughts on why I would have such a different response from cycle #1? All 3 cycles were done in 2011.Would you suggest trying a different protocol? Do you think I may be a good canidate for Micro-Flare Protocol?In both 2nd and 3rd cycles my e2 level was 22 and 24 at suppression check compared to 59 in cycle 1. Any insight? Could this mean that I am oversuppressed? Also AFC was lower in past 2 cycles.How much time do you suggest in between fresh cycles?Any thoughts that you would be willing to share would be greatly appreciated. I am getting very discouraged and you have been so helpful in the past. Thank you, D. from Massachusetts


Hello D. from the U.S.(Massachusettes),

It is difficult to critique protocols and I generally do not. There are many different ways to accomplish the same thing so any one particular protocol may not be better than another.I do not favor the long protocol, however, for two reasons. I think there is too much ovarian suppression at the beginning of the stimulation and you have to take many more injections. For that reason I use the antagonist protocol, which usually only required 2-3 injections. So, I would not go back to the long protocol. There is not question that the long protocol is the classic method, in fact, most REI's use this protocol because they are not familiar with the antagonist protocol.

In terms of your stimulation, there can be significant differences from one cycle to the next. For example, I have a patient who only produced one follicle in her first cycle with the maximum dosage of medication, yet in the second cycle, with a reduced protocol, she produced 8 follicles. This shows that each cycle is unique and the ovaries will respond differently. You don't mention of these cycles were done back to back i.e. consecutive months, but in general there should be a one month rest period between IVF cycles to allow the ovaries to recover. A stimulation of 12-14 days is not unusual and sometimes preferable. Sometimes a short stimulation phase leads to less quality eggs. Also keep in mind that you were successful in the second cycle, which means that you can be successful again. You have to be persistent. You are lucky that you are in an insurance mandated State for IVF.

I would strongly recommend against the Micro-flare protocol. This has been shown to not be of any benefit.Finally, there are other reasons for failure of an IVF cycle. You are young and had good embryos to transfer. So maybe it was something else? Implantation failure can occur if the transfer technique is not good by the Physician, as an example. Or you may need some additional meds to reduce your immune response or increase blood flow. There are differences between IVF clinics/centers. We are not all the same and therefore pregnancy rates differ.

Follow-Up Question #1:

Thank you so much for your thorough response. I have a few more follow up questions if you do not mind...What are your thoughts on the Estrogen Priming Protocol? Do you usually use a FH and FSH while stimming? I have read that adding Menopur in too soon can effect egg quality. The article that I read suggested adding it in after 4-5 days of stims and then lowering the FSH dosage. Any thoughts on this? My current RE had me starting Menopur on the 2nd day of stims.The past 2 cycles fertilization was only 50% with ICSI compared to 100% my 1st cycle. The embryologist noted that my eggs were "brownish". Any thoughts on this? Do you think it was due to egg quality? Lab issues?You mentioned additional meds to reduce your immune response and increase blood flow... what type of meds do you usually prescibe?How much emphasis do you put on SART scores.

I am contemplating switching clinics and I am looking for some guidance. Mass General has the highest success ratings in my age group but I have heard that they are very focused on scores, etc. I have heard great things about a RE at Boston IVF but there SART scores are lower. Would this be a deciding factor for you?Yes, I agree... I am very lucky to have insurance coverage! Again, I really appreciate your help. This process is so stressful and I am so overwhelmed!

Follow-up Answer #1:

Hello Again,

Let me take your questions sequentially for ease.

1. I don't have any feelings one way or the other regarding estrogen priming. I don't use it because I don't think it has been shown to be of any benefit. By I lack the experience to know for sure.

2. I am a believer in the "mixed protocol" which uses both pure FSH and a combination FSH/LH (my preference is Follistim/Menopur). Many studies have shown benefit to having LH present in the follicular phase. It has been found to increase the egg quality although there is not real technology to determine egg quality. I was trained on this method and my experience has been that the stimulation is better i.e. higher number of follicles. My pregnancy rates are pretty good as well. I don't agree that it will decrease egg quality. That has not been my experience.

3. Brownish or discolored eggs signify a basic egg quality issue. This may be why the fertilization rate was not as good. The minimum fertilization rate should be 50% and will vary from cycle to cycle because the eggs will be different each time. I don't think anyone has any explanation for why the eggs would have a "brownish" or "discolored" appearance.

4. I use low dose aspiring (81mg), Medrol (16 mg) and low dose heparin (2000 units twice per day). These all start with the start of the stimulation and continue through the cycle. The aspirin and heparin are stopped on the day of the trigger injection and not restarted until the day after the retrieval.

5. SART scores are certainly one thing I would look at. The problem with SART scores or the CDC scores is that they only look at one year, not cumulative scores which is more revealing. That's because clinics can have a good year and bad year depending on the types of patients they have, embryology problems, change in personnel, etc. But since these two organizations don't give cumulative statistics, you might have to ask the clinics if they have them. If you are going to use SART scores, then try to look at the last three years and compare. Also the problem with these scores is that they are 2 years behind and IVF technology is ever-changing.

Also, if you are going to look at the SART/CDC stats, the only one you should look at is the implantation and pregnancy rates per cycle and transfer in patients under the age of 35. Don't necessarily look at your specific age group. Those two statistics are the important ones and we use under 35 years old as the gold standard because those are inherently the most fertile patients (ie no age factor). Certainly your age group statistics are also important because you want a clinic that does well with your age group. If I were going to a new area and had no idea which clinic to go to, I would use the SART/CDC statistics to help me decide. Then I would go check them out, ask about their program and see how personal the care is (just like you would if you were buying a car). I don't recommend going to a factory type program. You want a program where you have one doctor attending you through the entire process and don't get a different doc for the transfer, which is one of the most critical steps. Sometimes smaller clinics are better than larger ones because of this, as long as the pregnancy rates are equivalent. Try to get the clinic's current statistics if you can or the most recent ones, and not necessarily the ones from two years ago submitted to SART. Most clinics will have the previous year's stats.

Follow-Up Question #2:

Thank you very much for your response. The info that you provided re: the SART scores is very helpful. I appreciate the tips!!One more follow up question re: the "mixed protocol". Do you usually start the Menopur at the same time as Follistim? Or do you wait a couple of days.Also, would you reccomend that I try any supplements? I have done some reading about DHEA? What are your thoughts?

Follow-Up Answer #2:

Hello Again,

The Menopur (FSH/LH) is started at the same time as the Follistim (FSH). I don't recommend any supplements. There are none, especially DHEA, that have been proven to work but I did see a recent article touting DHEA is older women. They claimed it increased embryo quality, but I am doubtful. That shouldn't be a problem for you because you are young.

Things that I do add in patents that have failed a previous cycle:
1. Acupuncture (it is not proven, but some studies show benefit and it doesn't hurt to try everything after failures.)
2. Low dose aspirin - 81 mg orally per day starting at the beginning of the cycle.
3. Low dose heparin - 2000 units SQ twice per day starting at the beginning of the cycle.
4. Medrol 16 mg orally per day starting at the beginning of the cycle and decrease to 8 mg on the day of transfer (you would stop this at the time of the pregnancy test).
5. Both progesterone injections and progesterone suppositories. I don't start the suppositories until the day after the transfer.

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

Comment: Dr. Ramirez is always very kind and helpful. I am very thankful for all of his help.


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  2. Hello Mr Ramirez,

    I am 32 yrs old and had my first IVF cycle in january 2012. no infertility cause could be established (male factor very good and yet unknown female cause). AMH levels are at 0.3 ng/ml, which is quite low.

    the IVF treatment was a long protocol, consisting of:
    1 gonapeptyl/ day from day 21 of previous period
    and bravelle for stimulation from day 3 , for 10 days: 3 bravelle / day in days 1- 8 of stimulation and 4 bravelle/ day in days 9-10 of stimulation.

    in the 7th day of the stimulation, i already had a bigger egg , 17 mm i think, and 4-5 smaller eggs.
    the endometrial lining was already a little bit thick on day 7 ( 9 mm, if i remember correctly) and got thicker by day 10 of stimulation (13-14 mm).
    estrogen levels in day 7 and 9 were not very high, so the doctor decided to increase the bravelle dose hoping to get a better response in terms of number of maturated follicles.

    however, the response remained poor - only 4 eggs could be retrieved on day 15 of my period, all fertilized, 3 resulted in category A 3 day embryos, but implantation did not occur.
    my period started one week after ET, even though i was on progesterone after egg retrieval.

    now, day 15 of my first period after the failed ivf cycle, my endometrial lining is 13-14 mm thick and my doctor says this is hyperplasia due to high estrogen stimulation and that i should wait and see how it progresses after the next period, if it does not get thinner, i should have a curettage.

    also, he recommends a short stimulation protocol for the 2nd ivf cycle.

    my questions for you are:
    is this hyperplasia a common occurrence after ivf (i could not find anything relevant on the internet)? is it a serious reason for concern at this point in time? my doctor said research has found that the estrogen in the stimulated cycle has toxic effects on the uterus. how bad can it get and what can i do to prevent that?

    how thick should the endometrial lining be at the time of ET in order to have greatest chances of implantation? was it too thick at my first ET? the fact that I had one early maturated egg influenced my period starting too early?

    could a short stimulation protocol give better results, in terms of number of eggs retrieved and lower endometrial thickening? is the quality of eggs poorer in the short protocol?

    thank you,

    Gabi from Romania

  3. Hello Gabi,

    It sounds like you did not have an adequate period and I don't believe that this is endometrial hyperplasia. I think the first thing I would recommend is to go through a quick medical D&C to shed the lining. This is done by taking a birth control pill 3 times per day for 7 days and should lead to shedding of the endometrium. That should clear that up. I cannot explain why the lining has remained if you stopped the progesterone as you should have after a negative pregnancy test.

    It seems that the reason for so poor a response was that your protocol was too low. It is hard to know how a patient is going to respond ahead of time so the doctor has to guess. It is usually an educated guess but until you actually go through the cycle, one cannot know for sure. In the next cycle, I would at least double the amount of medication. I am also a big proponent of the "mixed" protocol using an FSH (Bravelle) plus an FSH/LH (Menopur) in combination. You might want to discuss that with your doctor, but since there is no single way that is better than any other, it will be up to your doctor to decide how to proceed.

    The "early period" was actually probably breakthrough bleeding and may be a sign that the progesterone supplementation was inadequate. Did you take your progesterone as injections or vaginal form because these are the recommended way. If you used it orally, that would not lead to adequate levels.

    I am not sure what your doctor means by a "short protocol" so I cannnot address tha question. Is he referring to the micro-flare protocol?

    Good Luck

  4. Hello and thank you so much for your reply!
    I did take vaginal progesterone, and the bleeding was heavier and longer than my usual period, I assumed it was due to the stimulation.

    I think the short protocol means that there will be no suppression starting with day 21 of previous period, and the stimulation would start in day 3 ...I am not sure however.
    anyway, I will go to another clinic the next time and they required for genetic testing for trombophylia and the test results came positive for A1298C heterozygous mutation of MTHFR gene (only this turned positive, the other mutations are negative).
    do you know how / whether this impacts my fertility?

    also, could the AMH low level (0.30 ng/ ml) be a reason for the poor response ? I read somewhere that women with low levels of AMH should not even go for IVF. what do you think?

    thank you again.

  5. Hi My name is Mandy
    I have had 3 failed ivf
    first ivf - had a laproscope cleared infection and mild endometrioses 2 months later did first ivf - long protocol - did not do transfer of eggs, transfer cancelled no explanation

    second - went to different clinic, 4 months later, changed medicine
    day 12 pregnant - day 18/ 19 bloods dropped said had chemical pregnancy

    3rd - 10 months later - had a bladder injection at the time of doing blood tests, they screened my factor 8 level and bloods came back that i have low factor 8 level, thining of blood and high protien in my blood
    so this time round, they gave me metocortin, to lower immune system, and on aspiration they gave me intralipid drip, (milk) and factor 8, then after egg transfer said i must take estofem, and 3 days later intralipid again, on day 11 - negative preg test

    Don't know what to think or try
    we thinking of maybe rather doing the iui route this time maybe all the meds and injections is too much for my body
    my lining seems to be a problem, my eggs were about 4 cell and my lining on transfer was 9 which apparently should be higher
    any sugestions? ate really well

  6. Hello Mandy,

    I can't give you any specific recommendations with reviewing your medical records to see what was done. The general information you have given me is not sufficient. I'm also a little skeptical about the clinics that you went to.

    In general, I am not a big advocate of going "backwards" in treatment. That is, I don't recommend going from IVF to IUI. I think you need to continue trying with IVF, but maybe find another clinic. Again, however, this is a general recommendation and without seeing what was actually done, I can't determine if you received adequate treatment or not. Certainly the transfer of a 4-cell embryo is not a good sign and the prognosis for getting pregnant would have significantly lowered.

    Good Luck.

  7. Hello Dr. Ramirez
    I really love your blog and appreciate your help

    I have large endometriomas on both ovaries 9cm & 6 cm, i did laparoscopy but they came back full size
    I did 2 ICSI one was failure the other was chemical pregnancy then did an FET that also resulted in chemical pregnancy
    Now i am stimming for another fresh cycle
    I always respond wel and produce 9-13 follicles and transfer @ day 5
    did many blood work to try to find out why implantation fails, but no specific reason
    Antithyroid antibodies that came in (high-normal) range and also MTHFR (also in high-normal range)

    I have a concern this time that m endometrium thickness came back 17.5 whaich i am afraid too thick but my dr. didnt comment on this

    i am now taking clexane 4000
    aspirin 81
    omega3 3times daily

    do you think anything else can help with implantation
    I am afraid of another failure or a chemical pregnancy

    Thank you

    1. Hi,

      I think you need to make a very important distinction. You've had pregnancies which indicate that implantation occurred. So, you do not have implantation failure. For some reason, the pregnancies did not continue beyond an early stage. That may be more of an issue with recurrent pregnancy loss. There is a specific workup that needs to be done for this, and may not be due to the endometriomas.

      Giving you more information would require a full consultation and evaluation, which is too much for here.

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

      Monterey, California, U.S.A.

      for additional information check me out on twitter with me at @montereybayivf and facebook @montereybayivf. Skype and internet comprehensive consultations now available via my website for those who want a more extensive evaluation that this site can accommodate



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