36 Yr. Old Has Repeated Implantation Failure With Great Embryos...What's Wrong?

Question:

Dear Dr,

We have just had our 4th failed IVF (in vitro fertilization).

Our history.  I am 36, my husband is 39. 1st pregnancy was in 2009 after 3 IuI's (intra uterine insemination) and clomid, but had to terminate at 15 weeks due to large enphaloceale (was a random genetic mutation)and my 2nd pregnancy with IUI was a success with a full term healthy baby boy.

Started with IuI's for 2nd child in 2011! We had 10 IuI's and now 4 IVF's.  Each IVF has been with icsi (intracytoplasmic sperm injection) and this time we had Embryo hatching. Last 3 transfers were 3 top grade 8 cell embryos each time on day 3.  I am not a great responder and only ever have 5-7 eggs, of which usually 4 fertilise.

I have had all the immunity checks done, my husbands sperm dna damage is within normal, fertilisation rate is good.  My ovarian reserve was also checked and the level was 1.0- My specialist said that he wasn't overly worried about the reserve for my age.  I have had a hysteroscopy and all normal.  I have been on various drug protocols and this last one was the long Lupron cycle with menapur.

We are just not sure what to do next?  Do we keep going, as my doctors are very positive and we have the finances. Are my doctors missing something?  Is there anything else we can do to improve our chances.  I am on DHEA and Royal Jelly, and my hubby is also on supplements.

I am writing from CapeTown, South Africa.

Thank you for your consideration, R.

Answer:

Hello R. from South Africa,

The exact cause of your failure cannot be known as there are still four steps your embryo has to go through in order to produce a pregnancy: embryo has to develop to blastocyst, the blastocyst has to hatch our of its shell, it then has to attach to the uterine lining and the lining has to grow around it.  As of now, there is no technology that can make this happen.  "Assisted hatching" is just making a defect in the shell so that the embryo can exit (hatch) more easily.

Something I always worry about when I have patients tell me they have failed multiple cycles despite good embryos, is the quality of the final step of the IVF process, which is the transfer.  You can have the absolute best and perfect embryos but if the transfer technique is not done well, then it will fail.  This has been shown by numerous studies.  Since you have been going to the same clinic, I wonder if that is not the problem, in which case, I would recommend that you seek out a different clinic.

One thing that I do with my patients that is not universally accepted but done by many of us, is to use a recurrent miscarriage protocol to reduce the immune system, thinking that a heightened immune system might be at fault.  For this regimen I add low dose heparin or lovenox, medrol, low dose aspirin, extra estrogen and extra progesterone (both injectable and vaginal).  I don't think that DHEA does anything so I don't use it.

At 36 years old, I have a 66% pregnancy rate in my clinic.  By two to three attempts with good 8 cell embryos, you should already be pregnant.  Your rate should especially be increased over other 36 year olds since you have been pregnant before.  For these reasons, I think the fault may lie in your clinic and not in you or your husband. 

Good luck in your journey to have a second child,

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

 

Monterey, California, U.S.A.

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.

Egyptian Fails One Fresh & One Frozen IVF Cycle: Advice On How To Improve Lining Thickness

Question:

Hi, I am 28 years old, married since 3 years, trying to get pregnant since 2 years. I had ectopic pregnancy since 15 months which ended by right laparoscopic salpingectomy. Then I tried clomid for 3 cycles, HMG induction for 2 cycles and I tried fresh IVF (in vitro fertilization) with long protocol.

I took 1 amp menogone , 1 amp fostimon 75 mg, 1 amp fostimon 150 mg/d. there was 36 mature follicles , all fertilized well, then 4 good embryos were transferred on 3rd day but ended badly on 5th week by blighted ovum.

Then I tried frozen embryo transfer by thawing the embryos and let them grow to the blastocyst stage. We got 14 good blastocyst from 19 embryos, then 2 hatched blastocysts were transferred. I took estrogen valereate 6 tab/d till endometrium thickness 8cm, then progesterone supp 800 mg/ d , aspirin 75 mg/d. but again a negative BHCG on due time.

Some history:

a) semen analysis is good with no abnormal forms or motlity
b) patent left tube by hysterosalpigogram
c) history of endometriosis discovered during laparoscopic salpingectomy.
d) good hormonal profile FSH, LH, TSH, prolactin, anti-phospholipid tests

Now I am planning to repeat but I still have 12 frozen blastocysts, but I need your advise because we thawed the 3rd day embryos from the first ivf , then let them grow till the blastocyst stage , then did the transfer the last time , then refreezed them again.

My question:

I am undergoing a new frozen cycle now. I take 6 tablets oral estrogen valereate/ day, 200mg sildenafil (viagra) vaginally/ day and vitamin e, aspirin, and after the endometrium reached 8.5 mm thickness on the 10th day stimulation, it decreased on the 13th day to 6 mm although I still take the same dose with no discontinuation, sure of the expiry date.

What is your explanation please, and what can I do to prevent cancellation of the cycle? If I continued the same dose is there any hope for restoration the thickness?

Please answer me because I am frustrated and breakhearted.

N. from Egypt

Answer:

 Hello N. from Egypt,

This is a protocol question, which I do not answer because protocols can vary widely and there is not only one way to do things. That being said, there is some general information that I can provide.

First, keep in mind that you have been pregnant with IVF and so can get pregnant again. IVF only gives you the opportunity to become pregnant, it cannot make you pregnant because there are still some natural steps that must occur on their own. Studies have shown that if you have gotten pregnant in the past, your chances of getting pregnant with IVF are higher. Also keep in mind that, just like trying to get pregnant on your own each month, it does not always work. Sometimes it can take several attempts before it is successful.

Second, it is well documented by studies that the best way to deliver hormones for IVF is either by injection, by patches or by vaginal delivery. Oral tablets can be used vaginally (you just push them to the very back). This helps with maximum absorption of the hormone and delivery to the uterus. Oral intake has been shown to be the worst way to give hormones for IVF because most of it is lost when it passes through the liver. I personally use patches, which most US doctors use, but tablets used vaginally is also a good option.

I would not necessarily cancel the cycle, because time can be taken to develop the endometrial lining further. It is only finalized once the progesterone is started. That is what determines the timing of the transfer, which for a blastocyst, should be on the 6th day after starting the progesterone. If you have not started the progesterone yet, you can keep using an increased amount of estrogen to get the lining to 9 mms.

Good Luck,

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

How Can I Overcome Implantation Failure After Failing Multiple Fresh & Frozen Cycles?

Dear Dr Ramirez,

I'm a 43 years old female (from Australia) and for the last 2 years have been unsuccessful with IVF (in vitro fertilization) after 3 stimulated cycles and 10 Embryo transfers. I produce a good number of eggs (approx 18) with a stimulated cycle of 300iU/day of Gonal F. This egg number usually decreases at each stage; eg of 19 eggs, 13 are mature to fertilise, 6 fertilise and finally 1 or 2 reach day 5 blastocysts which can be transferred or frozen. All frozen eggs have always thawed well and transferred.

The pattern each cycle is similar however I'm finding that in this latest cycle only one embryo was transferred and the 2 remaining did not reach an acceptable stage for freezing. Implantation has always failed, even with the use of progesterone pessaries after transfer. I've also tried implanting 2 embryos with no positive result.

My specialist has resigned to the fact that my eggs are not of good quality due to my age. No testing on this has been suggested.

In terms of health I have PCO's and have a BMI of 30 (90kgs). I find it difficult to lose the weight which has been gradually gained in the last 8 years, have mild anxiety on the odd morning upon waking and trouble getting quality sleep 2 -3 nights per week. At times I suffer from low mood but put it down to the drugs and loss of hope. But I pull though with the support from family but use no medication. I do take a prenatal multivitamin 150mg of CoenzQ10 and fish oil. In your experience are there other treatments that could be explored for recurring implantation failure? Thank you, S. from Australia

Answer:

Hello S. from Australia,

Based on your embryo development and transfer of at least one good blastocyst, the cause of your failures is not determinable. We classify this as implantation failure but in reality there are two steps that have to occur naturally after the embryo is transferred. These are embryo hatching and attaching to the uterine wall and the endometrium growing around the attached embryo (implantation). We have no way to confirm that these steps are occurring. For that reason, there are no specific therapies to overcome failure at this point, but there are many suggestions for things to try. I say "things to try" because these are not proven remedies either. Also keep in mind that IVF success is not only dependent on embryo quality/normality and endometrial processes, but also on the doctor's transfer technique.

I think that what I would do if you were my patient is:

(1) Abandon the blastocyst transfer. Blastocyst culturing does not guarantee a quality embryo or success. Laboratory techniques, media, etc are not perfect. I wholly believe that the uterus is a better culture media and environment than the lab. Also, some embryos that might be the normal and healthy ones may not develop to blastocyst, as has been shown by numerous studies looking at preimplantation genetic screening.

(2) You could consider PGS to determine which embryos are genetically normal, and therefore have the highest chances for success.

(3) I empirically add low dose aspiring 81 mg per day, Medrol (Prednisone) 16 mg per day and Heparin 2000 Units twice per day starting at the beginning of the IVF cycle in my patients that have had repetitive failures. This is a formula that has been proven to decrease recurrent miscarriages with the thought that adequate micro blood flow and immunological factors may be leading to failure. I also increase my progesterone supplementation by using both injectable and vaginal supplementation, and add estrogen supplementation after the transfer by patch. Acupuncture has also been found to increase success in some studies, possibly by increasing blood flow or by reducing stress. All of these latter treatments are, as I said earlier, unproven. We call it "throwing the kitchen sink in" which basically means trying everything under the sun.

Finally, if you really suspect that it is an embryo problem, then donor embryos would be the remaining option, or you could consider using a surrogate if you think your embryos are okay but the uterus is not hospitable (my presumption is that a diagnostic hysteroscopy was already done to make sure of this).

Keep trying and 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.

Implantation Problems & Causes Of Chemical Pregnancy

Question:

Hi again, it's K. in NY. I have written to you in the past about my difficulties staying pregnant. I have had 7 chemical pregnancies in the past 18 months and one miscarriage at 9 weeks after using femara (you felt it was probably due to a respiratory virus I contrated around 6 weeks). I tested positive for MTHFR mutation heterozygous but also this didn't appear to be the issue.

I guess I have a 2 part question for you. The first would be related to causes of chemical pregnancies. My progesterone levels have been on the low side of normal (even during the pregnancy that ended in miscarrige) and I really thought that was the cause. I was placed on 50 mg suppositories 2 months ago and I did get a positive result this month (8 DPO Hcg 12, progesterone 18.8, took femara and progesterone) but my HCG level was back to <5 on 10 DPO.

Are there other implantation issues that could be my problem besides chromosomal abnormalities and low progesterone that lead to a pregnancy not progressing? I know I shouldn't test early, but I was trying to establish if low progesterone levels were the cause of my losses.

Part 2: is it possible to just have an underlying HCG level that elevates above 5 regularly, and if so, what would that signify? As you may remember, my old RE wrote off the HCG values as me eating too much cereal and developing an antibody to HCG that triggers pregnancy tests. I will be visiting a new RE soon and want to be sure to ask the right questions and supply the best information.Thank you very much for all of your insight and for volunteering your services. Merry Christmas!

Answer:
Hello K. from the U.S. (New York),

Let me take the second question first since it is the easier of the two to answer. The answer is NO, you can't have an underlying HCG level from cereal or any other source other than pregnancy. Serum pregnancy tests are very sensitive and testing for the beta subtype (bHCG), so there is no cross reaction even if the cows you were using the milk from were given hormones for some reason (I presume that is what your old RE was thinking as a source. A little far fetched if you ask me).

In terms of your chemical pregnancies, that is a difficult problem to answer. If you have already undergone a complete recurrent miscarriage evaluation (hormones, infectious diseases, anatomical, genetic, immunologic) then we may not have the technology to find the exact cause. However, the hormonal is easy to check through blood tests, and I automatically place my patients on progesterone supplementation just in case; anatomical testing would take an ultrasound and hysteroscopy, again an easy test; and infectious diseases and genetic are also easy to test. The only one that is difficult and not completely understood is the immunologic component. Many authorities have looked into many different immune factors.

If you look at a website by Reproductive Immunology Associates, who have made a practice of the immunologic causes of miscarriage, you will see lots of different test that they recommend. Because this component is so difficult to define, experts have conflicting opinions.

If you were my patient, I would put you on a protocol that I use and, for the most part, have been successful with. It involves taking aspirin 81 mg per day starting at the beginning of the cycle, medrol (prednisone) 16 mg per day taken from the beginning of the cycle then decreasing to 8 mg after ovulation, progesterone vaginal suppositories beginning after ovulation and, finally, heparin 2000 units twice per day subcutaneously beginning at the start of the cycle. The aspirin, medrol and heparin treat for subclinical immunologic problems and the aspirin and heparin also help to increase blood flow at the microvascular level at the implantation.

Good Luck & Merry Christmas to you too :) ,

Dr. 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 SO much for your opinion. I will definitely have to look into these additional things. Glad to hear that I am doing all that I can do on my own and that I am advocating for the right things. It makes a HUGE difference when you have an idea what direction you should be headed so that you can work with a doctor to get there. Merry Christmas!

A Little Miracle...Seven Years In The Making

I want to share a special story with you, my readers, about a couple who went through a recent IVF (in vitro fertilization) cycle with us. This couple had come to us back in 2004 for infertility treatment. After the normal trial of IUI's (intra uterine insemination) did not work, they opted to do IVF with us. The cycle went well, the retrieval went well and there were three embryos to transfer. While doing the transfer of all three embryos, one embryo "floated" (aspirated) back out of the catheter. This was an unusual event for me and my staff. The couple decided to freeze that one reluctant embryo. Unfortunately, the patient did not become pregnant with that cycle. As it so happens, she soon became pregnant naturally and in the ensuing years, as sometimes happens, they had no trouble conceiving again, having three children in all.

In the meantime, the frozen embryo remained in our cryobank storage facility. The couple elected to leave the embryo there for the last seven years until recently. Grappling with the options of either continuing to pay for storage, dispose of the embryo or put it up for adoption, the couple opted to go forward with a frozen embryo transfer. We transferred the one embryo successfully and crazy as it may seem, the patient is now pregnant! This child will be both the "oldest" and the "youngest" sibling by virtue of this unusual series of events.

I am a spiritual man, if you have not guessed already. For us, every child is special, but I have a feeling that this child will truly be a special one, for it is my belief that for some divine reason his or her birth was delayed. How often I feel defeated when a cycle does not succeed and yet when something like this happens, I know that we can only do what we can up until a certain point, at which time the final steps of creation are taken out of our hands. Which brings me to one of my favorite quotes from Deepak: "When you live your life with an appreciation of coincidences and their meanings, you connect with the underlying field of infinite possibilities."

Patient Fails One Fresh, One Frozen IVF Cycle: Will Another FET Work?

Hello,

My name is S. from Boston. I am writing with a question regarding what I am going to be undergoing next week, a second frozen transfer. Just to give you some history, I had a first attempt successful IVF (in vitro fertilization) cycle in 2008 and delivered a healthy baby. We are now trying for baby #2 and had an unsuccessful fresh cycle, and an unsuccessful frozen cycle in the last few months. I still have several frozen embryos so my insurance is mandating that we use them prior to doing another fresh cycle.

I know the success rate is lower with frozen embryos but I wanted to know another opinion, if I should proceed with a fresh cycle if this one is negative. I have 3 frozen embryos left, that are all 6 cell and high implantation potential. I am not optimistic that this one will work, because the other two cycles they put in 2 8 cells and they didn't take. My doctor says there is no difference between 6 and 8 cell embryos, but if that is the case, then why do they always choose to transfer the 8 cells first? I know I could also lose some cells in the thawing process, so does that lower my chances more, and are there are risks associated with the baby, if I do become pregnant this cycle? Thank you so much!

Answer:

Hello S. from the U.S.,

These are very good questions that you should direct to your doctor. It is his/her responsibility to keep you informed.

Let me take the easy questions first. The reason why we use the 8 cell embryo first is because embryos are graded based on their appearance. Yes, that is we give them a higher grade, the better they look, just like a beauty contest. The cell number is the number of cells the embryo has divided into by that particular day, which I presume to be post-retrieval day#3. Again, we prefer embryos with more cells than less cells. That does not necessarily mean the embryos with more cells are BETTER than the embryos with less cells. In fact, preimplantation genetic testing often shows the opposite. So a higher number of cells does not guarantee a good embryo. The factors that make a good or perfect embryo are not things that we have the technology or knowledge to apply at this point in time. Maybe in the future. My preference is for my embryos to be between 6 cells and 8 cells at this point. Most pregnancies will result from embryos within this range, either grade I or grade II.

Frozen embryo transfers have a lower pregnancy rate probably because the lesser embryos are left to be frozen and the better embryos are transferred fresh. Also, it may be because of the freeze and thawing of the embryos, but the technique has gotten so good that I don't think that is much of a factor any more. But, that does not mean that a frozen embryo can't implant and produce a good pregnancy. I would still recommend that you use them first before another fresh cycle because the medications required are less, AND there are some studies that show that implantation is better if there is no ovarian stimulation, as in Donor cycles. That might be an advantage. You just have to hope that the embryos are still good enough.

I might suggest that you ask your doc to culture the embryos remaining to blastocyst stage. That will be a further validation of the embryos, and may lead to fewer embryos to transfer, but they will be at a stronger stage. That does not necessarily give you a better chance at pregnancy, but the assumption is that if the embryo can survive further culturing then it has a better chance of continuing to implantation. That way, you can further screen the remaining embryos that you have. The ones that don't make it to this point will be discarded, then you will need to move to a fresh cycle. If you have extra blastocysts, you should only transfer two max at this stage, they can be frozen and are in a better stage for the freezing.Finally, there are no added risks for a normal baby if by frozen eggs or embryos. If the embryos are abnormal they usually will not work (implant) or will end in miscarriage. You have not given your age, but this can be a factor in terms of embryo quality, success and genetic risks as well if you are 35 years old or older.

Good luck,

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

Grading Of Embryos At Blastocyst: How Does It Reflect Implantation Rates?

Question:

My husband and I recently went through our first IVF. We have been trying for 2.5 years to get pregnant and have done 6 failed IUIs. We have stage 2 endometriosis that was cleared out by a laparoscopy last Fall. Aside from that we are unexplained infertility. We retrieved 10 eggs and 9 fertilized naturally. We transferred 2 blastocysts on Day 5 that were graded 2BB and 3BB at transfer. We had 5 others that made it to freeze on day 6.

I have been a little stressed out about the quality of the blastocysts. I know that 4AA is the highest. Will our blastocyst quality impact implantation rates? R. from the U.S.

Answer:

Hello R. from the U.S.,

The answer to your question is yes and no. It is ambiguous because grading does not necessarily predict whether implantation, pregnancy or a successful delivery will take place. I have often been surprised when I get a pregnancy from embryos that are "graded" as poor quality. I have also seen cases where when we do genetic testing called PGS (preimplantation genetic screening) the test results reveal that the good quality embryos are abnormal and the real bad one is normal! So I don't think you can say that the way your blastocyst are graded will necessarily have any impact on their ability to implant.

At this point in time, we do not have the technology to evaluate embryos fully to know which ones will implant and which ones won't. As far as I'm concerned, all embryos have the potential to implant and lead to a successful pregnancy. In my opinion, only God knows for sure. It is a good sign that you had embryos to transfer and freeze...Good luck with your transfer results!

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.

37 Yr Old Failed Two IVF Cycles, Has Frozen Embies And Husband With Slow Swimmers: What Would You Suggest?

Question:

I just failed my second IVF (in vitro fertilization) procedure. I am 37 years old living in the Bay Area. My husband has slow swimmers and not great morphology either. We used ICSI (intra cytoplasmic sperm injection) with both IVF procedures.

The first cycle I had 8 eggs, 6 fertilized and only two made it for transfer. The second cycle I had nine retrieved, 8 fertilized and we transferred two embryos on day 3, one an 8 cell and one a nine cell. We were able to freeze 3 embryos, not of as high quality. I believe the frozen embryos are 5 and 6 cells. I am planning to use the frozen embryos, but it seems like a lost cause as the quality of the embryos are not as good as the fresh ones that were transferred. I am doing acupuncture treatments as well.

Any advice would be most helpful. L. from San Francisco, California

Answer:

Hello L. from the U.S.,

I am sorry to hear of your failures, but IVF is certainly the best treatment for you based on your husband's problem and your age.

Without reviewing your IVF records, I cannot give you any specific information regarding your cycles or chances. Keep in mind that each IVF center uses different protocols and methods and pregnancy rates vary. For example, my pregnancy rate in your age group with ICSI is 56% per attempt with 41% continuing pregnancies. Pregnancy rates are very dependent on the stimulation, how many mature eggs are retrieved, embryo development and transfer technique. In addition, in your age group, having failed one IVF cycle already, I would have placed back all four embryos, even though the lesser celled ones were not as good quality. There is no utility to freezing them, and the prognosis with those embryos is not good as you already know. The success rate of a frozen embryo transfer cycles with good embryos is approximately 30%. Your best chance, once you have tried with the frozens if you choose, is to keep trying with fresh embryos.

In my protocol, I would probably place you at the max stimulation protocol, add low dose aspirin, low dose heparin, medrol and increased progesterone with the next cycle. Acupuncture certainly does not hurt and I would recommend that you continue it. On a side note, when my wife & I went through IVF she was 37 like you. We also did ICSI. She had 14 eggs retrieved, eight fertilized, and we ended up with one nine cell, one eight cell and the other two 5 cell. After conferring with her RE, (she was under the care of my colleague at the time) we decided to transfer all four. She became pregnant with a singleton, our daughter, who is now a healthy young teenager (her baby picture is on the Doctor's Background page of my blog). Needless to say, we did not regret our decision :)

Good Luck on your journey, I will keep my fingers crossed for you both!

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

Monterey, California

Can Progesterone Be Given With Clomid Induction? PCO Patient With 3 Failed Cycles Wants To Know...

Question:
I'm 31, never pregnant. Dx PCOS, receiving metformin 1500 mg a day. Three cycles with clomid with no ovulation. HSG normal, husband semen analysis OK. Now going through second cycle of IUI (intra uterine insemination), ovulation stimulated with Gonal F and triggered with ovidrel.

First cycle progesterone level on day 3 after second IUI was low (2.3), so I asked the doctors why they can not prescribe progesterone to improve luteal phase and make implantation more possible, and they told me they do it only with IVF. Is this Ok? What I mean is, why don't give progesterone if the level is low, and it is know than low progesterone impairs implantation and also increases risk of miscarriage in first trimester? Please give me some advice, or some reference articles where to read about this (scientific articles to support my request) Thank you! S. from Arkansas

Answer:

Hello S. from the U.S.,

You have a very valid question and you should ask your doctor why they don't give progesterone after intra-uterine insemination. I'm sure there are many articles on the web that you could find that advise this technique. There is absolutely no reason not to give progesterone after IUI or even after simple ovulation induction.

However, I think that your thinking may be incorrect, however. If the ovulation induction were proceeding correctly, and ovulation occurs, then the hormones should be corrected and there should be a normal luteal phase. Usually a mid-luteal progesterone is not to see if there is adequate progesterone for implantation, but to see if ovulation in fact took place because if it did not, the progesterone would be low. So you see, rising progesterone levels occur from ovulation. If the progesterone is low, that is an indication that ovulation did not take place and replacing progesterone would not have anything to help i.e. no implantation would occur any way.

I have to wonder about the protocol that your doctor is using, and I would suggest that you look at my blog under how I do clomid induction cycles. One specific technique that I use is to follow the follicle(s) with the ultrasound to determine when ovulation is going to occur. That way, I can better time the insemination. I also give an HCG trigger. Then I start progesterone the day after the second IUI (I do two IUI's per cycle) for luteal phase support. This is mainly because progesterone is an easy medication to use, is not expensive and has no adverse reactions/side effects/harm to the pregnancy. It can only help and increased progesterone is one of the main stays for the treatment of implantation failure due to inadequate b-integrin levels.

Maybe you should ask your doctor why he uses it for IVF and not for IUI? The reason to use it should be the same.

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.

Woman In Tasmania Has Done 14 IVF Cycles At One Center And Now Faces An FET: What Advice Can You Give Me?

(**If the blog-talk radio starts up, go to the October 1st blog post below & pause it...I will be keeping the show up for the month of October.)

Question:

Dear Dr Ramirez,

Someone wrote a comment on my blog suggesting I ask you. Basically, I was asking what questions to ask my RE. This is the post she was responding to:

Here’s where I am: I’ve been doing IVF/ICSI since July 2006. We started because my husband had a vasectomy many years ago, so it’s not like we’d been trying for years and didn’t know what was wrong and needed a diagnosis. We knew we’d need IVF if we wanted any hope of having a child.

I live in Hobart, Tasmania. There’s one clinic with only 2 REs: one who is part-time (he’s mainly an obsetrician) and one who is full-time. We started off with the part-timer but have been with the full-timer for a few years now. I would say they pretty much don’t have individualised treatment. They have a few standard protocols, but mainly seem to pride themselves on keeping treatment costs low so patients can have many cycles. Quantity, not quality. If you have repeated failures, they don’t do investigations; they just suggest you keep on going on.

To go to another clinic would cost us money, time, more stress, and be logistically difficult. That’s not to say I’m not up for it if need be. However my husband gave me the ‘I’m tired of treatment and would rather not pursue it, but I’m doing it for you’ bombshell the other night. So I don’t know if I could drag him by the testicles to an interstate clinic to try to get different treatment. I’m willing to go without him though. Having a child has become muchmore important than my marriage.

The only investigations I’ve had are a laproscopy, hysteroscopy, hydroscopy a couple years ago (I had endo, which was removed, and the hydroscopy as inconclusive as fluid didn’t move through my tubes but they looked OK). My obstetrician ordered a bunch of blood tests after Blobby’s miscarriage: protein C, protein S, AT 3, Anticardiolipin antibodies, LAC, Factor V Leiden, Prothrombin G20210A mutation MTHFR C677T mutation, MTHFR C677T mutation, and Karyotyping.I find it unbelievable that after so long, they still don’t try to find out WHY we’re having the problems we’re having. They never check hormone levels (not even during stim cycle – he just relies on ultrasounds to tell him what’s happening), they don’t check for implantation issues, there’s been no renothing. Hearing about the testing that goes on in other clinics has really opened my eyes. I would welcome finding out I had a problem because then we’d know whether it would be likely to be able to be fixed or if we had no hope.

Questions I’ve come up with are:

1. As one of our embryos is a 3 day and the other two are 4 day, can the 3 day be thawed used this time and thawed a day ahead? That way if it doesn’t thaw we still have 2 more we can attempt thawing.

2. Is there a wait list for donor semen? (There wasn’t a few years ago when I did 7 DI/IUI cycles, but I think there is now. Want to know just in case.)

3. Might DHEA help my embryo quality?

4. Any news on the egg donor wait list (Australia's)? (This is probably a stupid question; I know other women in Australia on the wait list and we all seem to get difference answers to our questions. Someone who is 27 was told recently she should have a donor by January 2011 – sorry, but that’s a HUGE porky she’s been told!)

5. The best embryo we’ve had was from a down regulation cycle. Is this just a coincidence, or should be try down regulation cycles again?

6. What sort of implantation failure testing can be done?

If you are interested, my blog "Riding The IVF Roller Coaster" is at http://tasivfer.wordpress.com/. I am writing from Hobart, Tasmania, Australia. Australia's island state - and a long way from any clinic other than the one I've been with for soooooo long. . .Cheers,TasIVFer

NOTE: As of 2012, TasIVFer is a MOM! "After 4 1/2 years, 14 fresh IVF cycles, 7 donor inseminations, 4 FETS, and the loss of my dear son Blobby at 14 weeks 2 days, we tried (half) an egg donor. Blood test 10 December 2010 = BFP. Little Spark was born 6 August 2011!!! He LIVES! Now the journey continues with an FET in November 2012 with our last embryo. Perhaps our last ever?" Good for her!!!

Answer:

Hello TazIVFer from Australia,

Let me take your questions in sequence and answer them the best that I can.

1. The Day #3 frozen embryo certainly can be thawed and cultured to align with the Day #4. My recommendation would be to thaw both, one day apart, and allow them to culture to blastocyst if your home lab has that capability. That may give the embryos a better chance of implantation. You don't mention what the cell # and grade was at the time of freezing but that is an important factor. As the saying goes, bad in-bad out. That means that if the embryo is poor quality, culturing further does not make it better quality. It may not survive the culture.

2. I cannot answer your questions regarding donor sperm wait lists. In the U.S., there are no donor sperm wait lists. Donor sperm are readily available. I guess that's because there are more men in the U.S. than Australia.

3. DHEA will do nothing and is not recommended. However, I would recommend that you consult my blog where I addressed the issue of implantation failure. I do have my own, specific protocol that I use for patients that fail IVF. Because I don't have any precise information from your cycles, I cannot give any specific recommendations.

4. Again, no egg donor wait lists in the U.S.

5. Coincidence probably but I would have to look at your cycle information to do a detailed analysis.

6. There are no specific tests for implantation failure.

I hope this answers your questions adequately. It is unbelievable that you have gone through so many cycles. I don't know of many women and their husbands that could manage the stress and frustration of prevailing through IVF for so long. I wish you the very best of luck with your FET cycle!

Keeping my fingers crossed! Good Luck,

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.

Paciente Con Endometriosis Severa Y Fracaso De Implantación FIV

I recently received a question from a woman in Mexico that addressed the problem of IVF Implantation Failure...I have decided to publish it in Spanish. Many who read this blog are Spanish speakers & need to translate the Q & A's. Since I speak Spanish, I would like to publish this one in it's entirety for my followers en español.

Question: Pregunta:

Dr. Ramírez.

Leí en la página web de su clínica de Reproducción que usted habla español. Agradezco mucho que se tome el tiempo de leerme y contestarme.

Soy L. de México. Tengo 29 años y mi esposo 33.

Lo busco pues estoy un poco desesperada... Llevo tres años en tratamientos continuos.

Mi padecimiento es endometriosis severa que afectó a mi reserva ovarica, actualmente tengo una fsh de 15. También mi esposo tiene astenoterato- zoospermia. Mi primer IVF (fertilizacion in vitro) fue con tres embriones día 3 de calidad II con hatching, y fue icsi - negativo. Mi segunda IVF fue con 1 embrión dia 3 de calidad II, con icsi, negativo. Mi tercer IVF fue sin estimulación ( sin medicamento alguno a diferencia de las otras dos), fue un IVF natural con un embrión que llegó a blasto día 5. negativo. Siempre al momento de la transferencia mi endometrio es aproximadamente de 12 mm y es trilaminar.

No se que estudios me recomiende adicionales pues creo que el problema puede estar en la implantación... o algo que me recomiende tomar adicional a la aspirina de 100 mg y la progesterona vaginal que me dan cada 12 horas siempre.

Agradezco de nuevo su tiempo. Saludos.

Answer: Respuesta:

Sra. L.,

Gracias por su pregunta y discúlpame que estoy tarde con mi respuesta.

Definitivamente, con su historia médica, fertilización in vitro (FIV) es la única opción por tratamiento porque este es la única tratamiento que puede cubrir endometriosis severa y la problema de esperma. Pero, un problema más grave es su reserva ovárica. Porque su fsh es 15, este es una indicación que los ovarios no están respóndanlo a la hormona fsh y la medicina que nosotros usamos por stimulacion es pura fsh. Por eso, el número de huevos aspirado es bajo y los embriones formo es minimo también. Pero, porque usted está joven, si la cualidad de los embriones están bastante, la posibilidad de embarazo debe ser máximo (es 73% cada vez en mi clínica con su edad). Por eso, usted está pensando que la problema es implantación.

La ultima dos partes del procesos para tener un embarazo en su cuerpo es saliendo de embrión de su piel (eclosión) y implantación junto con el endometrión. Fertilización in vitro (FIV) no puede controlar o cambiar este dos partes. Todavia es natural. Este parte es en la mano de Dios. Pero, muchas diferentes cosas pueden afectar la posibilidad de implantación. Por ejemplo, el técnico de su doctor es más importante. Usted puede tener embriones perfectos pero si el técnico para transferir los embriones es malo, el tratamiento no va a funcionar. Por esta razón, una opción que usted tiene es para cambiar su doctor o clínica. Mi profesor siempre me dijo que usted puede tener embriones perfectos pero si usted no se transfiere los embriones en la matriz perfectamente, todo es por nada. El tratamiento no va a funcionar. Este parte es la parte más importante!

Pienso que usted ha tenido un histeroscopia para confirmar que la cavidad de matriz y salio normal. Correcto? Si no ha tenido este estudio, yo recomendó que usted tiene esta estudio para ser seguro que no tiene nada anormal adentro. (La histeroscopia es un método de diagnóstico que consiste en introducir una lente a través del cuello del útero para visualizar la cavidad uterina.) Si usted tiene confianza en la técnica de su doctor y el procedimiento de transferencia de embriones paso bien, esta es un problema más difícil. En esto caso, yo recomendo usando aspirina 81mg cada día empezando con el ciclo de tratamiento, medrol 16mg cada día empezando con el ciclo de tratamiento y bajanda el dosis en el día de transferencia a 8 mg, estrogeno adicional como climara 0.2 mg parche o estradiol pastillas vaginal y heparina 2000 mg dos veces al día o lovenox 35mg por cada día. Todos empieza con el tratamiento y continua hasta el resultado del estudio por embarazo.

Últimamente, si Usted continua a tratar por un embarazo y tiene embriones con calidad buena, usted tendrá un embarazo. Buena Suerte!

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

American In The UK Taking Clomid & Has Thin Uterine Lining: Needs A Specialist

Question:

Hi Dr. Ramirez,

I will try to keep this as concise as possible. I am very healthy, slim and 29 years old, and have never had issues with my periods. My husband (29 years also) and I conceived on our first try last year, but unfortunately had a missed M/C at 12 wks (fetus stopped growing at 8 wks). Tests confirmed non-recurring genetic abnormality. After the D&C I had only spotting, until 5 days after when I had a very heavy bleed with large clots lasting only one day. Then I got my first period 6 weeks later. The 3 subsequent cycles were 42-45 days.

Pelvic ultrasound revealed PCOS, hormone levels were all normal, including thyroid. Lining on this ultrasound was only 5.5 on day 40, just before I started my period. I have just completed one round of 50 mg Clomid unmonitored due to travel, and BBT shows clear ovulation on day 18 with 12 day luteal phase. This cycle I have had my first follicle tracking on day 11 which showed dominant follicle at 15 mm, but lining of only 4 mm. My questions are:

1. Could the thin lining be due to problems from the D&C?

2. My gyn prescribed Progesterone pessaries for the second half of this cycle to help thicken the lining- is this the appropriate treatment?

3. When should I consider seeing a fertility specialist?

Thank you for your time- I am writing from London. M.

Answer:

Hello M. from the U.K.,

A thin lining could certainly be due to an over-vigorous D&C, leading to scarring in the uterus. This is called Asherman's syndrome. A procedure called hysteroscopy can be done to evaluate the uterus cavity for this. However, that being said, it is not very common to develop this with D&Cs. The more common possibility is a thin lining due to the use of Clomid.

Clomid is an estrogen receptor blocker and so blocks estrogen receptors at the endometrium (uterine lining). For that reason, many patients have to use extra estrogen given vaginally in order to overcome the blockage from the Clomid, or they use a different medication such as Femara or injectables.

Progesterone is NOT the hormone that thickens the uterine lining. Endometrial thickening and priming is dependent on ESTROGEN in the first half of the cycle. The fact that your doc told you the wrong info makes me skeptical that he/she clearly understands the physiology of this treatment. So, I think you should go see a fertility specialist instead. Without proper estrogen priming, the uterine lining will not be ready for implantation. The progesterone, which is given after ovulation, is to convert the endometrial lining to develop the "pinopodes" that are necessary for implantation. (See diagram up above, the "pinopodes" are small finger-like protrusions in the endometrium) Without the proper priming, the pinopodes will not develop.

Good Luck and keep trying, you should succeed with the right treatment path,

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 Dr. Ramirez! I am very grateful to have your opinion, which confirmed to me that I need to see a specialist. As an American living abroad, it can be daunting to find the same quality of health care that we take for granted in the US. Again, I really appreciate your help.

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.

IVF implantation failure

Questioner: Sophie
Subject: IVF implantation failure; luteal phase brown spotting, even with high progesterone levels Date

Question:
Dear Dr. Ramirez,

I have found your responses to others extremely helpful!

I am 35 years old and am writing from Hungary. My husband
and I've just finished our second, unsuccessful round of IVF
with ICSI; both were 5th-day transfers with a good quality
pair of embryos in each. My husband had had two samples
frozen before his BMT several yrs ago, which is what we used
for the IVFs--it looks like now he occasionally has a
nonmotile cell or two, but not much else.

I would very much appreciate your thoughts and advice on
luteal phase issues, including luteal phase support during
IVF, given a potentially short luteal phase and pre-cycle
brown spotting.

The first round of IVF, I got progesterone suppositories,
but my prog. level was fluctuating with that (was as low as
18.85 9 days post-transfer, and was up to 43 3 days later).
As a result, bleeding started 7 days post-transfer.

For the second IVF (with frozen embryos), I got progesterone
injections instead, which kept my prog. level up (56, 65).
Nonetheless, I still had definite brown spotting starting 4
days post transfer, gradually turning rust-colored. Both
transfers, I had mild cramps on days 2 and 3 after the
transfer.

As we were making preparations for the IVF, my fertility
doctor determined that I have a relatively short luteal
phase despite the fact that my cycles are 28-31 days long: I
ovulate on the 17th-21st day (20th is typical). In addition,
for the past three years, my period has always been preceded
by 1-4 days of brown spotting. And *including* those
spotting days, my luteal phase has been 9-12 days long
throughout 2009 (13 days when I was on Suprefact for the
ovarian stimulation).

A further detail that could be relevant: I have an
autoimmune thyrod disorder that is being monitored, no
medications for it. My anti-TPO level is 1516 and I have a
thyroid cyst about 3x2x3 cms in size, the biopsy was
negative. My thyroid levels have been normal: TSH 0.65-1.2,
T4 15.6.

Any thoughts on what might be behind the persistent pre-
cycle spotting, despite the high prog. levels with the
injections, and what can be done about it?

I would like to do all I can to exclude the possibility that
the embryos did not implant because of a luteal-phase-
related issue, especially because the number of chances
we've got are limited. Do you have any suggestions what
might be worth asking about, any variations on the protocol,
any further tests? Right now, the plan is to do the 3rd IVF
round--with potentially the last batch of frozen sperm--with
the same luteal phase support as before: ovitrelle for the
ovulation and prog injections, following a stimulation phase
consisting of suprefact and gonal-f 150. I am told that
based on my low HCG level ( 0.1) measured at 12 days post
transfer, the embryos did not even begin to implant in
either of the previous rounds. So the spotting in this
second round wasn't due to implantation then.

Also, I have read about taking vitamin B6 for luteal phase
defect, my doctor here says he doesn't know about that
helping with the short luteal phase and the spotting. What
are your thoughts on the matter?

I very much appreciate your time and help.
Yours sincerely,
Sophie

Answer:
Hello,

Thank you for all the information and the very well written letter. I can't even tell that you are from Hungary. Your English is perfect!

First of all, despite the fact that you may have had a luteal phase defect in the past, the purpose of the progesterone after retrieval is to treat for possible luteal phase defect. Therefore, you don't have a luteal phase defect with your IVF cycles, and this is NOT the reason for the implantation failure. Something else must be going on. You don't mention the quality of the embryos, but that would be one question. Also, you don't mention how many were retrieved, how many fertilized, how many did not make it to blastocyst and how many were frozen. I presume there were none to freeze since you don't mention it.

Implantation failure is a difficult problem because we are not able to distinguish all the processes required for implantation, and there are not tests to help. The only current test available, b-Integrins, don't help because the treatment is to use more progesterone. I would do that any way. Please read more on implantation failure and recurrent miscarriage here: "Recurrent Pregnancy Loss".

My approach to patients with implantation failure is to add the following medications:

1. Aspirin 81 mg per day beginning at the start of the cycle.
2. Heparin 2000 units twice per day beginning at the start of the cycle.
3. Medrol 16 mg daily until transfer then 8 mg from that point until positive pregnancy, then stop.
4. Increase progesterone to 50 mg injection plus Endometrin 100 mg twice per day vaginally. The injections starts on the day of the retrieval and the suppositories start the day after the transfer.

This regimen covers most immune responses that might prevent implantation, as well as, any micro-clots that form at the site of implantation. It is used mainly in patients that have recurrent miscarriages, but has proved useful in IVF as well. You might want to suggest this to your doctors. This regimen is unproven and controversial, however. Another suggestion would be to transfer at day # 3 instead of going to blastocyst. Blastocyst culturing is not perfected, and I still believe that the uterus is a much better culture media and incubator that the lab.

Also keep in mind that pregnancy rates are very clinic dependent. There is a wide variety of pregnancy rates between clinic, and the rates can very much be influenced by the laboratory environment, the physician skill doing the transfer and the stimulation and culture protocols. One option might be to try a different clinic. I recently changed my clinic location and our pregnancy rates are much better than before because we were able to build a better facility.

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