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.

40 Year Old IVF Patient In Vietnam On Low Protocol Fails First Cycle: Has Many Questions, Concerns

Question:

Dear Dr. Ramirez,

My name is A. from Vietnam, 40 years old by end of March 2011. Just give you some information about me regarding Infertility/IVF. My menstruation cycles are different every month: 28 days in Feb, 26 days in March and 31 days in April. So, average: 26 days. Period in March was especially longer; maybe it was caused by hormone therapy in March. My FSH on March 6 (2.day of period) was 10.6mIU/mL and AMH on April 9 was 0.8ng/mL.

I started my first IVF cycle on March 6 2011 (2. day of period) and ended it with 2 embryos transferred on March 22. Unfortunately, it failed. On March 6, I got 1 Decapeptyl 0.1mg. However, I reacted allergic to this and the doctor stopped Decapetyl and gave me 2 days later on March 8: 1x Gonal F 300 i.u. each day and for 8 days until March 15. One day later on March 16, I got Pregnyl at 8.30pm. 2 day later on March 18 at 8.30am, I had my egg retrieval. 6 eggs were collected and 4 were fertilized. On Day 3 after retrieval at 8C stage I had 2xnormal embryos with grade 1, 1x embryo with grade 2 and 1 embryos with Monosomy 21. On day 4, 2 embryos were transferred. My husband semen test result shows 25% normal form (morphology) with total live count of 341 million sp/vol and has anti-sperm antibody. So, I used IVF, ICSI and PGD (for down’s syndrome) in March.

For the next IVF: One clinic suggested to give me on the 3.day of my menstruation 1x300 i.u. Gonal-F mornings and 1x 150IU Menopur nights for 4 days first. Based on the follicle count and size in the ovaries, they will decide on further dose. They are likely to follow a step-down protocol. They will not use any drugs like Decapeptyl this time.

Another clinic suggested to give me on the 2nd day of my menstruation 1x300 i.u. Gonal-F for 5 days and will see based on the ultrasound result.

Could you please kindly answer my following questions and tell me what would you do differently?

1. Do I need birth control pills? Why or why not? I think I need it, because my monthly cycles are different. So, with the birth control pills, the embryos will be implanted on time. What do you think?.

2. Which dosage and drugs would you use except for the 2 dosages of 2 clinics?. Which dosage of these 2 clinics does make more sense to you? Which one will give me more eggs with good quality? Last IVF, I just had 6 eggs, 4 fertilized and just 2 healthy embryos transferred at the end. As I know, I need 3 embryos for my age.. Do I need such kind of drugs like Decapeptyl? Why or why not?.

3. On which day would you start the IVF (2. or 3.Day of period)? Why?.

4. Will acupuncture and Chinese herbs support the success of IVF? Or will it be contra productive? If recommended: before or before and during the IVF? I am taking prenatal multi vitamin and 400mcg folic acid. Do the unfreezing eggs have the worse quality compared to fresh eggs?

5. Was the embryos’ transfer late (at the Murola stage) last time? Should it be transferred earlier this time at 8C stage? I will not use PGD this time. Did I have enough eggs (6 eggs last IVF) at my age? Do I need to increase them next time? Does one embryo have 9% success rate for women at 40?

Thank you very much for your time. Best wishes.

Answer:

Hello A. from Vietnam,

It is interesting for me to see that IVF is being done in Vietnam, proving that this is a procedure that spans the world. Keep in mind that protocols used are highly variable between clinics and doctors. No one protocol is better than another so the recommendations I give are based on my knowledge, experience and preferences.

I always use the birth control pill preceding an IVF cycle. I believe the studies that show better response to stimulation by using the BCP. In addition, it causes the ovaries to essential shut down so that they will be more responsive to the stimulation and so that the follicles will start out somewhat evenly when the stimulation is started.

One thing I noticed about the protocols you have been on is the fact that they are low dose protocols. My highest protocol is a total of 600IU of FSH and I prefer a "mixed" protocol using pure FSH and an FSH/LH mixed compound. The preferred medications I use are Follistim (pure FSH) and Menopur (FSH/LH) in an approximately 2:1 ratio. So, my highest protocol, which is what I would use with you, is Follistim 450IU and Menopur 150IU taken every evening. My highest protocol is a continuous protocol, meaning you stay at the same dose all the way through, but it will really depend on your stimulation. Sometimes, if the patient stimulates more strongly than expected, I will drop the dose but most patients with an elevated FSH like yours (decreased ovarian reserve) will stay at the same dose. I do think that you were understimulated and the number of eggs retrieved and resultant embryos was low. In your age group I would prefer to have 4-6 embryos to transfer.

I cannot comment on the two clinic's protocols specifically, as I mentioned earlier. I can only give you my opinion regarding the protocol that I use.

In my center, I start the IVF cycle on an arbitrary day called "cycle day #2" irregardless of when your period actually starts on that cycle. This is because having used the birth control pill, I am in total control of the cycle and don't have to rely on the natural cycle timing.

I do recommend acupuncture as some studies have shown it to be beneficial with IVF.

I do think that the transfer should have been on D#5 post retrieval if PGS was done (blastocyst) but if PGS is not going to be done, then D#3 is better because I believe the uterus to be a better culture environment that the lab. Frozen embryos tend to have a decreased pregnancy rate, mainly because the best embryos are used to do the fresh transfer and the second best left to freeze. Also, the freeze/thaw have a little effect on the embryos but if done right, this should not be significant.

Finally, pregnancy rates are highly variable between doctors, clinics and countries. I cannot compare them exactly. In my center, your chances of pregnancy per cycle is 70% with 60% continuing. The U.S. does tend to have higher pregnancy rates than most other countries. At 41 years old, this decreases to 47% pregnancy and 29% continuing. Since we batch pregnancy rates into a 38-40 yo category, the rate I gave for 40 years old might be a little higher than it should be.

"Chúc may mắn"....Good luck on your next cycle!

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.

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

IVF Patient Asks: What Supplements Can I Take To Increase Implantation Success?

Question:

Good day Dr Ramirez,

I was wondering what supplements and vitamins can I take to increase my chances of implantation in an IVF cycle?

Thank you! V. from the U.S.

Answer:

Hello V.,

There are no natural supplements that I know of that can help with implantation. I do add aspirin 81mg per day, Heparin and Medrol to my patients that have had implantation failures or failed IVF cycles because these meds have been shown to increase endometrial oxygenation and decreased miscarriage rates. Before you use these, however, it should be done in consultation with your IVF doctor so that you are not going against any protocols that he/she may be using.

In addition to supplements, you may want to look into doing acupuncture. While I cannot endorse the procedure on a purely scientific basis, some research has been done to see if acupuncture does have a beneficial effect with IVF patients. My patients are always given this option and a referral to local acupuncturists who specialize in infertility.

One in particular here in Monterey, Rikke Blessing (http://www.blessingacu.com/), has referenced some studies you may want to look at. This one was published in 2002 in Fertility & Sterility, the medical journal of reproductive medicine. "Researchers in Germany have looked at acupuncture to determine its efficacy with the use of traditional TCM combined with assisted reproductive techniques with embryo transfer (IVF). The acupoints chosen were used to relax the uterus. The main purpose of the study was to evaluate whether acupuncture accompanying embryo transfer increases clinical pregnancy rates. The results showed that the pregnancy rate for the acupuncture group was considerably higher than the control (42.5% acupuncture group versus 26.3% control group)".Paulus, W., Zhang, M., Strehler, E. Influence of Acupuncture on the Pregnancy Rate in Patients who Undergo Assisted Reproduction Therapy. Fertil Steril 2002;77:4;721-24

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.