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

Two Failed IVF - LOW AMH

Questioner: SA
Subject: Two Failed IVF - LOW AMH

Question:
Hello. This is a followup from June 22nd. Recap: 39 attempting for 11 months. Jumped into assisted treatment due to maternal age. 3IUI and 2IVF (both rounds all eggs fertilized and went to blastcyts) results 8w pregnancy from the 3rd IUI and two chemical pregnancy results from IVF. We have no known issues given multiple testing and family history outside of maternal though have a low AMH (1.3/pmol). Recent Laprosphy showed tiny polyp at entrance to uterus which was removed. Gearing up for next round of IVF will be 375 Gonal F stimulation (usually 9 follicles w/ 2-3 fertilized - all mature eggs always fertilise). Discussed using DHEA within clinic which they had no issue. Implantation due to old eggs seems to be the most resonable answer. What other options can I consider to make this round successful?

Kind Regards (am located in London but am American)

SA

Answer:

Hello,

As you know, every clinic has differing protocols. I certainly have mine. There is no treatment for "old" eggs. The advantage of IVF is that you can stimulate the ovaries so as to get out many many more eggs that you can naturally. This is with the hope that there will be one good egg in that crop. If not, you have to keep trying until you find one. You are still relatively young so there will still be some good eggs left.

Once my patients fail a cycle, I do what I call a "full court press." This means I give them everything under to sun to cover everything that I can and give them the best chances that I can. There are no studies to justify this, but it is all that I can do. In some cases it is successful and in others not. I would treat with a maximum protocol which is Follistim 450/Menopur 150 taken daily. I do not split the doses, but some clinics do. This is to try to stimulate the ovary to give a maximum number of eggs. Remember the goal is to find that one good egg left in the ovary so we need to get as many eggs out as possible. I also use the following:

Aspirin 81 mg daily beginning from the start of the cycle.
Heparin 2000 IU twice per day beginning from the start of the cycle.
Medrol 16 mg daily until the transfer then decrease to 8 mg until pregnancy test.
I use BOTH injectable and vaginal progesterone (double up).
Climara patches 0.2 mg (two patches) weekly beginning at the time of retrieval (estrogen supplementation).

I do not use the "long protocol" which is starting Lupron on day # 21 of the preceding cycle, or the "flare" protocol which is starting Lupron on cycle day # 2. I avoid ovarian suppression until the follicles are 17 or 18 mms then use Ganerelix (antagonist). This is to allow the ovaries to stimulate as strongly as possible (again to maximize the yield).

If you were coming to my clinic, this is what I would do. But each doctor has his own philosophy regarding these regimens, so yours may not approve.

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.

Female orgasm and conception

Question:

Hi:

This might sound like a silly question, but here goes. My husband and I have been trying to conceive. A friend of mine recently told me that if a female has an orgasm either during or after the male ejaculates, this can improve the odds of conception as the contractions of the uterus that occur with orgasm help tip the cervix towards where the pooled sperm and propel the sperm into the uterus. However, she continued, if a female ejaculates before the male her vaginal fluid can actually harm her chances of getting pregnant. When my husband and I have intercourse, he will always allow me to reach orgasm first and only then will let go. I'm just wondering whether my friends' info is just an old wive's tale or is scientifically proven. Could the fact that I have an orgasm prior to my husband's ejaculation stopping us from conceiving? I enjoy my current sex life very much but would switch things up a bit if need be :)

Answer:

Hello,

I'm afraid your friend's recommendation is a new one for me. It is neither scientific nor logical. It is possible that orgasm would help with sperm motility into the cervix, by virtue of uterine contractions, but that is not a necessity. Many women do not have orgasm and still get pregnant. Also, the fluid within the vagina and cervix are conducive to sperm survival, if it is the appropriate time in the cycle.

My only recommendation is for you to continue to enjoy your sexual activity and technique. If you are trying to conceive then timing is the key, not position, climax or resting after. If you don't' achieve pregnancy by 1 year and have been timing the cycles well and ovulate, then something else is wrong. You should then seek an evaluation.

Interestingly, at the turn of the 20th century, doctors used to manually induce orgasm i.e. masturbate the patient, as a treatment for infertility, PMS and other female disorders. Of course, it didn't work too well so we don't do that anymore. Just thought you might enjoy that bit of trivia. :)

Sincerely,

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.

Pregnancy After Tubal Ligation

Questioner: genna
Subject: what are my chances of having another child

Question:
when i had my tubes tied after having my second child i was only 24yrs and the doctor said that within five yrs their was a chance that my body will heal and the tube will go back the way they was is that true is it true for the body to heal its self and is their anything i could do to try and conceive again?

Answer:
Hello,

If the tubal ligation was successful, the tubes will not "grow" back or "heal itself". That is the purpose of a tubal ligation. It is a permanent sterilization method. Because of your age, I would not have done a tubal on you. You were much too young.

You have two options for getting pregnant: (1) tubal reversal surgery. This is a microscopic surgery whereby the tubes are repaired and sutured back together. If it is successful, then you would have the ability to become pregnant naturally and repeatedly. You will need to use contraception again to prevent pregnancy if you don't want more kids. In the best hands, the chances of pregnancy are up to 70% per year of trying. The down side is you won't know until after the procedure has been done and the risks are that the tubes will scar together, or you will get a pregnancy that lodges in the tubes (called an ectopic pregnancy), which is a surgical emergency. Also, whether or not it can be repaired is dependent on the method that was used in the tubal ligation to begin with. The more damage that was done to the tube, the less repairable it is.(2) In Vitro Fertilization. In this case, the ovaries are stimulated and the eggs are removed directly from the ovaries. Fertilization and embryo development then occurs outside of the body in a specialized laboratory. The tubes are bypassed with this procedure. In general, it has a much higher pregnancy rate per attempt. In under 35 years old, you would have a 60-70% chance of pregnancy with each attempt. Nowadays, most people will do IVF because of the higher chances of success.

Both cost approximately the same so most will go to IVF. Beware of doctors that do tubal reversals but don't do IVF in their centers. They usually will counsel to do the surgery but not counsel regarding the option of IVF. On the other hand, most IVF centers will do both, but beware of the ones that don't even mention the surgery.

Good Luck,

Edward J. Ramirez, M.D., FACOG

Irregular Menstrual Cycles and Progesterone

Questioner: Cat
Subject: progesterone cream and spotting

Question:
Hi Edward, you have helped me before and I have another question. I am currently using progesterone cream (after having post pill amenorrhea) 14 days on and 14 days off. Last month I started my period early (on day 8 of the cream)n and it consisted of brown and back blood. This month I am having spotting again on day 7 of the cream, brown again. Why did my period never turn into an actual "red" period last month? And why does it keep starting early? Shouldn't it start a few days after I stop the cream (the drop in progesterone triggers period)? Thanks for any help you can give me!

Answer:
Hello,

The treatment you are receiving may not be appropriate for your problem and now you are having "breakthrough bleeding" from the progesterone. The cyclic progesterone only works if you have ovarian function that produces some estrogen and grows an endometrial lining. If that doesn't happen, then the progesterone will not work appropriately and you will have the BTB.

Post-pill amenorrhea is a description and not a diagnosis. More than likely you reverted to your normal ovarian function after stopping the pill and that "normal" function was an ovarian dysfunction. That is, the ovary was not previously working properly so it went back to not working properly. The most common ovarian dysfunction is PCOD. In this case, the hormone precursors, fSH and LH don't get processed correctly within the ovary and so estrogen and progesterone are not created, mainly because the ovary does not go through an ovulatory cycle. Because estrogen is not adequately created, the endometrial lining is not developed and hence, there is nothing to bleeding after progesterone, or very little to bleed. In this case, you should be on the birth control pill to cycle you normally, not progesterone. If you are trying for pregnancy, then you need to go on a fertility medication to stimulate your ovary to ovulate. The best birth control pill for PCOD patients is called Yasmin or Yaz because the progesterone component, blocks the testosterone receptors, which is a hallmark of this abnormality (elevated testosterone).

Sincerely,

Edward J. Ramirez, M.D., FACOG

Failed IVF Question

Questioner: Claudia
Subject: 2nd failed IVF - what now?

Question:
Good afternoon Dr. Ramirez,

I had my 1st failed IVF (10.08) on the flare lupron protocol: 7 eggs retrieved, 5 mature, 4 fertilized, 1 blast + 1 morula d5t, ICSI and assisted hatching.... chemical pregnancy
Yesterday, I experienced my 2nd IVF failure using an antagonist protocol (Ganirelix): 16 eggs retrieved, 13 mature, 10 fertilized, 3 (8 cells grade 1 & 2) and 1 (7 cell grade 2) embryos d3t, ICSI.... BFN

I just turned 39 yrs old and I'm intimidated about future IVF cycles before I don't have clarity on the issues that may have gone wrong? We were diagnosed with unexplained infertility and advanced maternal age, however, I produced a good # of eggs the 2nd time, my uterus lining was above 9 mm each time, I have open tubes and no thyroid, CF issues (tested 08/08).
I'm just wondering if you have any additional tests in mind or suggestions I could consider before going into another round? I really appreciate your response, thanks beforehand.
Claudia

Answer:
Hello,

It sounds like both IVF cycles went well as far as the controllable aspects of the treatment. The second cycle was better because of a higher yield. In the second cycle, out of the 10 fertilized, only four were of reasonable quality. That is the "age factor." We know that with increasing age, less of the eggs will be internally good and lead to abnormal embryos. Despite the fact that your transferred embryos looked good, they still have a high probability of being chromosomally abnormal, hence the chemical pregnancy and failure. This is what happens with age. You need to understand this because, the age problem is not reversible. What it means is that you have to keep trying until there is finally a good egg that makes a good embryo leading to pregnancy. It will eventually happen, it will just be harder. If you want a shorter course (i.e. less attempts), then donor eggs would be the only alternative, but the chances of pregnancy will be higher (73% per attempt this year in our clinic).

The protocol I use with my older patients, especially if they have failed previously, is to use a high protocol (I call it C8c which stands for a continuous 8 amp (600IU) antagonist protocol (the c was for Cetrotide but now I use Ganerelix). The 8 amps is broken down into 450IU of Follistim and 150IU of Menopur on a daily basis.

I also add the following:

Medrol 16 mg per day
Climara patch 0.2 mg per day starting at retrieval
Heparin 2000 Units twice per day starting at the beginning
Aspirin 81 mg per day starting at the beginning
Progesterone 50 mg injections starting at retrieval
Endometrin 100 mg twice per day starting after transfer

Your docs may have their own protocol for previous failures, or may not want to do this same protocol, but it is an option.

These do not treat abnormal eggs nor make them better. They do help with implantation, however, and reduce the immune response a little. That is why I use them. It is a full court press protocol. The bottom line is to keep trying. That is the only way you are going to be successful in the end. If you don't try, you definitely won't be successful with IVF.

Sincerely,

Edward J. Ramirez, M.D., FACOG