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.

Canadian IVF Cycle Fails: Husband Asks, Try Again?

Question:

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

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

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

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

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

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

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

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

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

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

Thank you,

T. from Ontario, Canada

Answer:

Hello T.  from Canada,

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

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

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

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

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

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

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

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

Good Luck,

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

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

 

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

Question:

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

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

2nd IVF/ICSI cycle

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

1-8 cell grade 1 (best)

2-8 cell grade

21-8 cell grade

32-7 cell grade

22-5 cell grade 2

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

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

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

Answer:

Hello M. from North Dakota,

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

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

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

Good Luck,

Edward J. Ramirez, M.D., FACOG

Executive Medical Director

The Fertility and Gynecology Center

Monterey Bay IVF Program

http://www.montereybayivf.com/

Monterey, California, U.S.A.

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

42 Yr. Old U.K. Patient With Poor Egg Quality, Tubal Damage, Given Troubling News: How To Proceed?

Question:

I am asking this question from the UK.

I am 42 years old, and have recently had a failed IVF cycle. It was my first IVF cycle and I had a low response. I had a total of 3 eggs harvested.

There were 2 from mature follicles and 1 from a small follicle. I know this is a poor response because I was on the maximum amount of drugs. I was on Buserelin 1mg/ml - 0.5ml per day, puregon 300 units and menopur 300 units per day. Not only did I have a poor response but the egg quality was also very poor. The egg from the small follicle burst before the embryologist could perform ICSI on it. The other 2 eggs did not change or develop in anyway when ICSI was performed on them. And ICSI was done because my husband's sperm is low in number and has problems with motility and morphology.

I recently had a follow up session with the fertility specialist and he advised me to not do any more IVFs and to consider egg donation if I want to proceed. And he even went on to say that even if by some miracle I did get pregnant my egg quality is so poor that the child would most probably have serious birth defects. I was so devastated.

My questions are I only had one IVF and the FSH on day 3 was 9.3, so can my doctor tell from one IVF that I have a low egg reserve and all my eggs are of poor quality. I forgot to say that both my tubes are blocked so an IUI wouldn't be useful.

Could it be that on another cycle an IVF might give better results? I have always had regular periods. Could my ovaries just have responded badly the first time and might they respond better to a second IVF? And most importantly, even if by some miracle I get pregnant, does my poor egg quality in this IVF cycle mean that a child would most probably have serious birth defects?

I want to do another IVF cycle. I want to see if a different drug protocol might cause a better result. Please tell me if you think that I should have any hope for a better result or if I must face the brutal truth that there is no hope and I must only consider egg donation.Thank you so much for taking the time to answer my questions.

ANSWER:

Hello P. from the U.K.,

In answer to your questions:

1. Low ovarian reserve (the stimulation response) and low egg quality are two different factors. You had both in this cycle. The elevated FSH of 9.3 is an indication that the ovaries probably will not stimulate very well with maximum stimulation as you did. It does not indicate poor egg quality,however. Your age is more of a factor indicating poor egg quality. As you know, pregnancy rates decrease significantly with increasing age, especially after 35. This is mainly due to poor egg quality. There is no way to correct poor egg quality other than trying to recruit and extract multiple eggs in the hope that a good egg will be present in that group. I don't think that all your eggs are poor quality but certainly the majority (90% or more) are.

2. There have been several studies on poor responders showing that each cycle is unique and yields a different result. So, there is still a chance, that even with one embryo, you could be successful in a subsequent cycle. However, to keep from giving you false hope, the chances would be low so you would need to be prepared for failure and to have to try several attempts. There was recently an article in the New York Times here in the U.S. about a 49 year old woman who conceived and delivered by IVF using her own eggs. I believe she is the oldest in the world to have done so (get pregnant with her own eggs by IVF). However, they were clear to point out that it took her two years of doing IVF to attain that success.

3. I disagree with your doctor's statement that if you got pregnant you would almost certainly have an defective child. Because of your age there is a strong risk for miscarriage or a genetic abnormality such as Down's syndrome. However, abnormal embryos rarely implant or lead to a successful pregnancy. The only reason Down's syndrome gets by is because it is a mild genetic defect (only one chromosome is abnormal). If you get pregnant, and it successfully progresses beyond 8 weeks gestational age, your chances are good of having a normal child. We do recommend genetic testing, however, for those few that are abnormal. Poor egg quality usually leads to an embryo with multiple abnormalities, poor embryonic development and either no pregnancy or an early miscarriage.

4. I don't see any reason why you can't keep trying with your own eggs as I mentioned above. I see miracles happen all the time. However, you have to be prepared for a bad result, and if you can handle that, go ahead and keep trying as long as your ovaries still respond. You can switch to donor eggs at any time and at almost any age (although we tend to limit it to below 50) so that option will always be there. That being said however, I would probably have counseled the same as your doctor because we want you to be successful in the shortest time, least amount of attempts, least amount of emotional cost, and least amount of financial cost.

Follow-Up Question:

Dr. Ramirez,

Hello, it's P. again.

My next question concerns trying to fix my blocked tubes.

I wonder if I should consider a procedure to have one or both of my tubes unblocked. I have read that sometimes a tube can be so scarred that even having a procedure to unblock it doesn't work.

If one of my tubes was unblocked and remained so, then I could become pregnant naturally, couldn't I? I know I would still be battling with a poor egg reserve and a lot of eggs that are poor quality because of my age. Do blocked tubes mostly remained blocked even after a tubal opening operation? I am also very overweight, will this make a difference to how easily a surgeon could perform such an operation?

Dr. Ramirez, do you think this could be an option for me? Thank you for answering my questions. It is truly wonderful that you give up your time to help women like myself. God Bless you for your kindness.

Follow-Up Answer:

Hello Again,

Despite what anyone may tell you, tubal damage is NOT repairable or reversible except for two exceptions:

1. The fimbriated end of the tube is blocked by scar tissue that was causes externally, such as by previous surgery or a ruptured appendix.

2. The opening to the tube at the uterus is blocked by mucous, in which case, an HSG can sometimes unblock them and they would function normally.

Anything else that caused tubal damage cannot be fixed, and surgery does not exist for this. In addition, because of your age and ovarian reserve, even if that technology did exist (such as tubal transplantation), your "natural" chances of pregnancy would only be 1% per year of trying. It definitely would not be worth the surgical cost or risks. IVF has a better chance of 25-27% per attempt.

Good luck, P. and don't lose heart!

Sincerely,

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:
Dr. Ramirez answered my questions clearly, completely and kindly. He obviously has a genuine desire to help women that find themselves in the terrible position of needing fertility help.

Is There A Link Between Late Ovulation And Miscarriage?

Question:

I recently read (in "Making Babies" by Dr. Sami David) that a follicular phase that lasts more than 20 days is a problem because it means the estrogen is building up too slowly which results in deterioration in egg quality and an increased risk of chromosomal abnormalities.

I recently experienced a missed miscarriage at 11 weeks. The cycle I conceived, my follicular phase was 30 days and I'm wondering if continued late ovulation could be increasing my risks of experiencing this again? Your thoughts?

J. from New York

Answer:

Hello J. from the U.S.,

I do not agree with Dr. David, and do not know where he would get that information. There is no relationship between follicular phase length and miscarriage. Most miscarriages occur because of some overt abnormality of the embryo or pregnancy, and usually are specific just to that particular pregnancy. Most patients with miscarriages will ultimately have a successful pregnancy.

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.

Twitter with me at @montereybayivf

Poor Embryo Quality: Donor Eggs Vs. Change Protocol Vs. Change Centers

Question:

I have undergone 3 IVF cycles without success in Canada. First IVF using long protocol, failed to stim and the cycle was cancelled. Subsequent 2 IVF cycles were done in flare protocol.

Of the flare cycles, first one was using Gonal F (450IU) and Luveris, we got 18 eggs, 13 mature, all 13 fertilized, but on day 3 only 2 had divided to 6-8 cells. All others arrested at 2-4 cells. Transferred 2 back with assisted hatching, but failed.

Second flare cycle was using Menopur (375IU), 13 eggs retreived, 8 mature, all 8 fertilized, but on day 3 only 2 were good enough to transfer, one that had started compacting, another at 8 cell, both were transferred back with assisted hatching, but failed again. All others divided will odd cells (3-5) and arrested on day 3. After the 3rd cycle, doctors suspect the egg quality to be very poor and advice us to use donor eggs. All blood/hormone tests are normal, left fallopian tube is blocked at fimbral end. I'm now 33, never been pregnant. My husband's results are normal.

Is this indeed due to poor egg quality? Is there any treatment available to improve egg quality? Is there any other IVF protocol that we can try that might give better results?Any advice based on your extensive experience is greatly appreciated.

Answer:

Dear S. from Canada,

Based on the information you gave me, you certainly did stimulate well in your second and third cycles. One option is to use a combination protocol with Gonal-f and menopur, and the antogonist (ganerelix or cetrotide), instead of lupron flare protocol. That may help with egg development and quality. There have been several studies showing the benefit of the combination protocol. The antagonist allows the ovary to stimulate and develop the eggs without being suppressed, as occurs with lupron. You'll have to ask your docs if they feel comfortable using an antagonist protocol.

There is no direct way to improve egg quality after fertilization. However, eggs/embryos are very sensitive to their environment i.e. laboratory quality. Any airborne gas or contaminant can effect them.

For example, in 2007 I had terrible pregnancy rates. In review, we found that in this year, the building where I had previously had my offices & center had gotten several new tenants and was doing a lot of remodeling. The air flow system in that building was not isolated and the air shared throughout all the offices. We had a very good Hepa filter in the lab but it could not isolate the air effectively with the huge change in parameters. Luckily, in early 2008 we moved our center to a new building where we are the only tenants. I was able to build my lab using the latest technology and air flow recommendations. My under 35 pregnancy rate went from 27% in 2007 immediately to 74%. The only difference was the air quality and control. Our lab is now in an isolated part of the building and does not share airflow with any other part of the office. Environmental controls and air flow have been studied and written about extensively in the IVF literature.

Certainly, if you are consistently having poor embryos, then the only alternative would be donor eggs. But before I would draw that conclusion, you might want to try a different center. Another experience I had was a patient who moved from Washington D.C. to California. She had gone through two IVF cycles there and, like you, had poor embryo quality and also was recommended to undergo donor IVF. But because her husband's job location changed, they moved here and she presented to me. Like you, she was young and I counseled that she should continue trying with her own eggs, at least two more times. Well, in her first cycle with me, she had three excellent quality embryos and became pregnant with twins (all three were transferred). It just goes to show not only that a different center could have a different outcome, but because we know that each cycle is unique, the outcome could be different from just having a different set of eggs and embryos.

I hope this helps,

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.